Delivery of oral drugs

ABSTRACT

Disclosed is a system for delivery of a drug comprising a multiple unit dosing device comprising a housing and an actuator, said device containing multiple doses of multiparticulates comprising drug particles, said device upon actuation delivering a unit dose of said multiparticulates, said drug particles having a mean diameter of greater than 10 μm to about 1 mm such that an effective dose of said drug cannot be delivered into the lower lung of a human patient. Also disclosed are novel methods, devices and dosage forms for delivering a drug.

FIELD OF THE INVENTION

The present is directed to a delivery device and method for the oraladministration of therapeutic agents in powder form for gastrointestinaldeposition.

BACKGROUND OF THE INVENTION

The most prominent mode of delivery of therapeutic agents is by the oralroute by means of solid dosage forms such as tablets and capsules. Oraladministration of solid dosage forms is more convenient and acceptedthan other modes of administration, e.g. parenteral administration.However, the manufacture, dispensing and administration of solid dosageforms are not without associated problems and drawbacks.

With the manufacture of solid dosage forms, in addition to the activeagent, it is necessary to combine other ingredients in the formulationsfor various reasons, such as to enhance physical appearance, to providenecessary bulk for tableting or capsuling, to improve stability, toimprove compressibility or to aid in disintegration afteradministration. However, these added excipients have been shown toadversely influence the release, stability and bioavailability of theactive ingredient. The added excipients are a particular problem withdrugs which require a high dose in order to provide a therapeuticeffect, e.g., biphosphonate drugs. The inclusion of the additionalexcipient can make the final tablet extremely large which could resultin esophogeal damage due to the physical characteristics of the dosageform if it is not swallowed properly. Esophogeal damage can also becaused by toxicity caused by the drug itself, if the tablet becomeslodged in the throat or has an increased transit time through theesophagus, due to its increased size.

Further, the tableting of certain drugs has many associated productionproblems. In particular, many drugs, e.g., acetaminophen, have poorcompressibility and cannot be directly compressed into solid dosageforms. Consequently, such drugs must either be wet granulated ormanufactured in a special grade in order to be tableted which increasesmanufacturing steps and production costs.

The adherence to good manufacturing practices and process controls isessential in order to minimize dosage form to dosage form and batch tobatch variations of the final product. Even strict adherence to thesepractices still is not a guarantee that acceptable variation will occur.

With the high cost of industrial scale production and governmentalapproval of solid dosage forms, such formulations are often available ina limited number of strengths, which only meet the needs of the largestsectors of the population. Unfortunately, this practice leaves manypatients without acceptable means of treatment and physicians in aquandary with respect to individualizing dosages to meet the clinicalneeds of their patients.

The dispensing of oral solid dosage forms also makes the formulationssusceptible to degradation and contamination due to repackaging,improper storage and manual handling.

There are also many patients who are unable or unwilling to takeconventional orally administered dosage forms. For some patients, theperception of unacceptable taste or mouth feel of a dose of medicineleads to a gag reflex action that makes swallowing difficult orimpossible. Other patients, e.g., pediatric and geriatric patients, findit difficult to ingest typical solid oral dosage forms, e.g., due totablet size.

Other patients, particularly elderly patients, have conditions such asachlorhydria which hinders the successful use of oral solid dosageforms. Achlorhydria is a condition wherein there is an abnormaldeficiency or absence of free hydrochloric acid in the gastricsecretions of the stomach. This condition hinders the disintegrationand/or dissolution of oral solid dosage forms, particularly dosage formswith high or insoluble excipient payloads

Flavored solutions/suspensions of some therapeutic agents have beendeveloped to facilitate the oral administration of oral agents topatients normally having difficulty ingesting conventional solid oraldosage forms. While liquid formulations are more easily administered tothe problem patient, liquid/suspension formulations are not withouttheir own significant problems and restrictions. The liquid dose amountis not as easily controlled compared with tablet and capsule forms andmany therapeutic agents are not sufficiently stable insolution/suspension form. Indeed, most suspension type formulations aretypically reconstituted by the pharmacist and then have a limited shelflife even under refrigerated conditions. Another problem with liquidformulations which is not as much a factor with tablets and capsules isthe taste of the active agent. The taste of some therapeutic agents isso unacceptable that liquid formulations are not a viable option.Further, solution/suspension type formulations are typically notacceptable where the active agent must be provided with a protectivecoating, e.g. a taste masking coating or an enteric coating to protectthe active agent from the strongly acidic conditions of the stomach.

Another alternative to oral dosage forms for certain medications isaerosol dosage forms which administer therapeutic agents for depositionto the pulmonary systern. The use of aerosol dosage forms has manyadvantages for the patient. The packaging of the active agent isconvenient and easy to use, generally with limited manual manipulation.As the medicine is sealed within the device, direct handling of themedication is eliminated and the contamination of the contents from airand moisture can be kept to a minimum. Further, a metering valve can beincluded in the device in order to individualize the dose for particularpatients. However, such formulations also have drawbacks such asdecreased bioavailability of the drug due to improper administration bythe patient. For example, if a patient's breathing is not coordinatedwith the activation of the device, the active agent will not reach itsintended site of action which will lead to a decrease in therapeuticbenefit.

Another alternative is dry powder dosage forms. For example,International Patent Application WO 94/04133, hereby incorporated byreference, describes a powder composition for inhalation which containsa microfine drug such as salbutamol sulfate and a carrier containing ananti-static agent. The carrier is calcium carbonate or a sugar,especially lactose. The amount of carrier is 95-99.99 weight percent.The compositions are said to be useful for delivery of the active agentto the lungs while providing reduced side effects such as nausea bymaximizing its proportion of drug reaching the lungs.

U.S. Pat. No. 4,590,206, hereby incorporated by reference, describescapsules, cartridges or aerosol containers containing spray-dried sodiumcromoglycate in finely divided and un-agglomerated form. A substantialproportion of the individual drug particles have sizes and shapes whichallow deep penetration into the lung and yet are free-flowing so as toallow capsule filling.

International Patent Application WO 93/25198, hereby incorporated byreference, is directed to an ultrafine powder for inhalation. The powdercomprises a drug and hydroxypropyl cellulose and/orhydroxypropylmethylcellulose. More than 80 weight percent of theparticles in the powder are said to have a particle diameter of 0.5-10microns. The powder is said to be able to reach the lower windpipe andbronchi.

Due to the disadvantages of known drug delivery discussed above (as wellas other disadvantages) there exists a need in the art for thedevelopment of a device and method for facilitating delivery of a widerange of therapeutic agents for gastrointestinal deposition and whichminimize pulmonary deposition of materials having undesirable or unknownpulmonary toxicology but which are approved for oral delivery.

OBJECTS OF THE INVENTION

It is an object of the invention to provide a method and system for thedelivery of a dose of a therapeutic agent in multiparticulate form forgastrointestinal deposition.

It is an object of the invention to provide a method and system for theoral administration of a dose of a therapeutic agent in multiparticulateform into the oral cavity of a patient for gastrointestinal deposition.

It is an object of the invention to provide a method and system for thedispensing of a dose of a therapeutic agent in multiparticulate form,for subsequent administration into the oral cavity for gastrointestinaldeposition.

It is a further object of the invention to provide a method and systemfor delivery of multiple doses of a therapeutic agent inmultiparticulate form which minimizes the need for inert pharmaceuticalexcipients.

It is a further object of the invention to provide a method and systemfor delivery of multiple doses of a therapeutic agent inmultiparticulate form for fast, standard, sustained, controlled, ortargeted release.

It is a further object of the invention to provide a method and systemfor the delivery of a dose of a therapeutic agent for gastrointestinaldeposition which protects the active ingredient from contamination andmoisture.

It is a further object of the invention to provide a method and systemfor the delivery of a dose of a therapeutic agent for gastrointestinaldeposition which allows for the dosing to be adjustable based on theneeds of an individual patient or patient population.

It is a further object of the invention to provide a method and systemfor the delivery of a dose of a therapeutic agent for gastrointestinaldeposition which can be used for a wide variety of agents for a widevariety of therapies, e.g. to treat systemic and/or local conditions.

It is a further object of the invention to provide a method and systemfor the delivery of two or more different drugs in multiparticulate formsimultaneously or at different times. The device of the system can holdthe 2 or more drugs in separate compartments or together in the samecompartment.

It is a further object of the invention to provide a method and systemfor the delivery of a dose of a therapeutic agent for gastrointestinaldeposition which provides an acceptable variability from dose to doseand batch to batch.

It is a further object of the invention to provide a method of producinga unit dose of a drug without limitation to the compressibility or doseamount of the drug.

It is a further object of the invention to provide a method and systemfor the delivery of a dose of a therapeutic agent for gastrointestinalabsorption which can be administered and swallowed without the aid of afluid.

It is a further object of the invention to provide novel oral dosageforms in multiparticulate form.

The above objects of the invention and others are achieved by virtue ofthe present invention, which in certain embodiments provides a drugdelivery system for delivery of a drug for gastrointestinal deposition.The system comprises a multiple unit dosing device comprising a housingand an actuator, the device containing multiple doses ofmultiparticulates comprising drug particles, the device upon actuationdelivering a unit dose of the multiparticulates for gastrointestinaldeposition, the multiparticulates having a mean particle size of greaterthan 10 μm and preferably less than about 1 mm in order to minimizepulmonary deposition of the multiparticulates and such that an effectivedose of the drug cannot be delivered into the lower lung of a humanpatient. The drug delivery system can be used to administer the unitdose of multiparticulates into the oral cavity of the patient (in-vivo)or to dispense the unit dose into an intermediate receptacle (ex-vivo)for subsequent gastrointestinal deposition.

In certain embodiments, the invention provides a device for delivery ofa drug comprising a housing and an actuator, the device capable ofcontaining multiple doses of multiparticulates comprising drugparticles, the device upon actuation capable of delivering a unit doseof the multiparticulates wherein the multiparticulates have a meandiameter of greater than 10 μm, and preferably less than about 1 mm inorder to minimize pulmonary deposition of the multiparticulates and suchthat an effective dose of the drug cannot be delivered into the lowerlung of a human patient. The device can be used to administer the unitdose of multiparticulates into the oral cavity of the patient (in-vivo)or to dispense the unit dose into an intermediate receptacle (ex-vivo)for subsequent gastrointestinal deposition.

In certain embodiments, the invention provides a device for deliveringmultiple unit doses of a drug in multiparticulate form comprising ahousing for containing multiple unit doses of a multiparticulatescomprising drug particles, the housing having an opening for deliveringa unit dose of the multiparticulates; a metering component operablebetween a first position in which it receives a unit dose from saidhousing and a second position in which it delivers the unit dose of drugto the opening in the housing; the unit dose being delivered from thedevice to the exterior of the device through the opening of the housingwith an air flow of less than about 20 litres/min. In preferredembodiments the device does not include a propellant to facilitate thedelivery of the unit dose and preferably the unit dose is deliveredthrough the opening substantially by gravitational force.

In certain embodiments, the invention provides a device for deliveringmultiple unit doses of a drug in multiparticulate form comprising ahousing to contain multiple unit doses of multiparticulates comprisingdrug particles, the housing having a mouthpiece for delivering a unitdose of the multiparticulates into the oral cavity of a patient; meansfor removing a unit dose of the multiparticulates from the housing anddelivering the unit dose to the mouthpiece, the mouthpiece having a drugreceiving end connected to the removing means and a drug delivery endthrough which the unit dose is delivered outside the device, themouthpiece being positioned on the device such that drug particlesexpelled through the mouthpiece can be deposited in the oral cavity of apatient substantially without deposition of drug particles into thelungs of the patient.

In certain embodiments, the invention provides a device for deliveringmultiple unit doses of a drug in multiparticulate form comprising ahousing to contain multiple unit doses of multiparticulates comprisingdrug particles; the housing having a mouthpiece for delivering a unitdose of the multiparticulates into the oral cavity of a patient; ametering component for removing a unit dose of the multiparticulatesfrom the housing and delivering the unit dose to the mouthpiece, themouthpiece having a drug receiving end connected to the meteringcomponent and a drug delivery end through which the unit dose isdelivered outside the device, the mouthpiece being positioned on thedevice such that drug particles expelled through the mouthpiece can bedeposited in the oral cavity of a patient substantially withoutdeposition of the drug particles the lungs of the patient.

In certain embodiments, the invention provides a method of preparing adrug delivery system for delivering multiple doses of a drug forgastrointestinal deposition comprising preparing a multiparticulate drugformulation in a manner to provide particles which when placed in theoral cavity and swallowed are deposited to the gastrointestinal tractand not deposited in any substantial amount to the lungs; and placingmultiple unit doses of said drug formulation in a device which meters asingle unit dose for delivery.

In certain embodiments, the invention provides a method of treating apatient in need of multiple doses of a drug for gastrointestinaldeposition comprising preparing multiparticulates comprising drugparticles in a manner wherein the drug particles when placed in the oralcavity and swallowed are deposited to the gastrointestinal tract and notdeposited in any substantial amount to the lungs; placing multiple unitdoses of the multiparticulates in a device which meters a single unitdose for delivery; and either (a) administering the unit dose into theoral cavity of a patient or(b) dispensing the unit dose into anintermediate receptacle and thereafter administering the unit dose intothe oral cavity of the patient.

In certain embodiments, the invention provides a drug formulation forgastrointestinal deposition comprising a non-compressed free flowingplurality of particles comprising a drug and a pharmaceuticallyacceptable excipient, the particles having a mean diameter of greaterthan 10 μm to about 1 mm, the particles comprising at least about 80%drug, preferably at least about 90% drug.

In certain embodiments, the drug formulation can further comprise afacilitating agent (e.g., an absorbability enhancer, a texture modifier,a taste masking agent, a sweetener, a flavorant, a salivary stimulant,an effervescent compound or combinations thereof) which enhances theoral administrability of the unit dose.

In certain embodiments, the drug formulation can further comprise amaterial to provide fast, standard, sustained, controlled, or targetedrelease.

In certain embodiments, the invention provides a method for delivery ofa drug comprising delivering multiparticulates comprising drug particlesvia the use of a multiple unit dosing device comprising a housing and anactuator, the device upon actuation delivering a unit dose of themultiparticulates, and thereafter re-using said device to deliveradditional unit doses of multiparticulates at appropriate dosingintervals, the drug particles having a mean diameter of greater than 10μm, and preferably less than about 1 mm to minimize pulmonary depositionand such that an effective dose of the drug cannot be delivered into thelower lung of a human patient. In certain embodiments of the method,upon actuation, the delivery is by administering the unit dose into theoral cavity of the patient (in vivo). Alternatively upon actuation, thedelivery is the dispensing of the unit dose into an intermediatereceptacle (ex vivo) for subsequent gastro-intestinal deposition.

In certain embodiments of the invention, greater than about 80% of theunit dose is deposited in the gastrointestinal tract, preferably greaterthan about 90% or greater than about 95%, and most preferably, about100% of the unit dose is deposited in the gastrointestinal tract.

In preferred embodiments of the invention, the unit dose comprises adiscreet collection of multiparticulates. For purposes of the invention,a “discreet collection” means that the multiparticulates are in the formof a non-compressed free flowing unit and not dispersed in a cloud ormist, which effectively minimizes inhalation of the active agent intothe lungs of the patient. The unit dose can be, e.g., from about 0.01 mgto about 1.5 g, depending on the dose of the active agent beingdelivered. For example, the unit dose can be from about 1 mg to about100 mg or from about 10 mg to about 50 mg. Preferably, the unit dose isadministered to the tongue, most preferably towards the front of thetongue behind the teeth, where it can be easily swallowed with orwithout the need for an additional fluid. However the invention doescontemplate delivery to any portion of the tongue, taking into account,e.g., the taste sensations of different sections of the tongue and/orindividual patient preference associated with comfort, e.g. mouthposition.

In certain embodiments of the invention, the mean diameter of the drugparticles is of a size which mininizes their capacity to be inhaled intothe lower lung. Typically, the agglomerate mean particle size of thedrug particles is greater than 10 μm, preferably greater than about 50μm or greater than about 75 μm. In certain embodiments of the invention,the mean particle size range of the drug particles is from about 100 μmto about 1 mm. In preferred embodiments, greater than 80% of the drugparticles have the above disclosed diameter (not mean diameter), e.g.80% of the drug particles have a diameter of greater than 10 μm, or adiameter of from about 100 μm to about 1 mm. In other embodiments,greater than about 90% of the drug particles have the above discloseddiameter.

In certain embodiments of the invention, the mean diameter of the drugparticles does not vary by greater than about 20%, preferably notgreater than about 15% and most preferably not greater than about 10%.

In certain embodiments of the invention, the multiparticulates comprisea pharmaceutically acceptable excipient. The excipient preferably doesnot comprise more than about 20% of the multiparticulates by weight,preferably not more than about 10% by weight.

In certain embodiments of the invention, the excipient is coated withthe drug, or the drug is coated with the excipient. Alternatively, thedrug and the excipient can be a mixture of powders, each preferablybeing greater than 10 μm, preferably greater than about 50 μm or greaterthan about 75 μm.

In certain embodiments of the invention, the excipient can provide tastemasking of the drug. In taste masking embodiments and other embodiments,the excipient can include flavors and/or sweeteners. In otherembodiments, the excipient can provide a sustained or delayed release ofthe drug.

In certain embodiments of the invention, the multiple doses of the drugare contained in a reservoir. The reservoir can contain an amount ofmultiparticulates to provide any number of unit doses, e.g. from about 2doses to about 400 doses. For ease in patient compliance, the reservoirhas a sufficient quantity of to provide e.g. a days supply, a monthssupply or a years supply of doses, e.g. 30 or 365 for once daily dosingfor a month or year, respectively.

In certain embodiments, the system can contain multiple dosingmechanisms in order to provide different dosage amounts for differenttimes. For example, the system can comprise two dosing mechanisms whichcan provide a different dosage amount in the morning and the evening. Inother embodiments, the dosing mechanism can be adjusted in order toincrease or decrease the size of the dose.

In certain embodiments, the system can contain more than one reservoir,each containing a different drug or enantiomeric form of drug. Uponactuation, the desired amount of each drug is metered out for delivery,such metering being present in the factory or other place, e.g., apharmacy. Such a system would be beneficial for combination therapy andwould eliminate the need for multiple systems and would allow a muchwider range of possible doses and dose combinations than heretopossible.

In certain embodiments of the invention, the system delivers up to about80%, preferably up to about 90% of the doses supplied in the system,thus eliminating waste by providing an efficient system.

In certain embodiments of the invention, the variability between dose todose is not greater than 5%. In certain embodiments of the invention,the delivery of the unit dose is facilitated by a gas, which may beprovided by the patients own breath maneuvers or which can be containedin the system in the form of pressurized gas or liquid gas.Alternatively, the delivery of the unit dose can be facilitated by aliquid carrier. In such an embodiment, the liquid and the unit dose aremixed during or after the unit dose is discharged from the reservoir.

In certain embodiments of the invention, the device comprises amouthpiece. Preferably, the mouthpiece is of sufficient length tominimize moisture exposure of the reservoir from outside the device.Preferably, the mouthpiece comprises a mouthpiece cap or closure tominimize the ingress of moisture (e.g., from saliva or humidity) intothe device. In order to minimize moisture exposure of the reservoir, theinvention can also include a desiccant. Further measures can be taken bymaking the device from a material which has water repellant propertiesto inhibit the accumulation of moisture. For example, the device canconsist of a non-wetting material such as silicone, which ifcontaminated with moisture, would promote the formation of dropletswhich would run off and not adhere to the surface of the device andwould not result in the accumulation of water. In certain embodiments,the device (especially the mouthpiece) can comprise a silver containingplastic or other material resistant to microbial growth.

In order to aid in patient compliance, certain embodiments of theinvention include a counter or indicator to display the number of dosesremaining in the system or the number of doses actuated.

In certain embodiments of the invention, the unit doses are individuallymetered prior to actuation, e.g., in the form of capsules or blisters,wherein each blister contains one individual unit dose. The system canbe capable of containing any multiple of pre-metered unit doses, e.g.from about 2 to about 400 blisters.

In certain embodiments of the invention, the system is capable of beingreloaded with additional doses (in reservoir or pre-metered form) uponfull or partial depletion. Alternatively, the system can be manufacturedwherein the device is disposable and is not capable of being reloadedwith additional unit doses.

The present invention is also directed to a method of administering adrug to a patient for gastrointestinal deposition comprising formulatingthe drug in multiparticulate form; containing the multiparticulates in adrug delivery device capable of delivering multiple unit doses of themultiparticulates into the oral cavity; administering a unit dose of themultiparticulates to the oral cavity of the patient wherein greater thanabout 80% of the drug is deposited in the gastrointestinal tract. Thismethod can be achieved, e.g., by controlling at least one at least oneof the following factors: a) formulating the multiparticulates to have amean diameter of greater than 10 μm; b) administering themultiparticulates with a device having a mouthpiece which directs themultiparticulates onto the tongue of the patient; c) administering themultiparticulates with a device which delivers the unit dose as adiscreet collection; and d) administering the multiparticulates with adevice having a flared mouthpiece.

The invention is also directed to methods of delivery (e.g., in vivoadministration and ex vivo dispensing) and methods of treatmentutilizing any of the disclosed embodiments directed to compositions ofmatter. The invention is also directed to methods of preparation of allof the disclosed embodiments.

The present invention is also directed to systems which containparticles greater than 10 μm of a particulate drug and particles of 10μm or less of the same or a different drug which upon actuation, delivera unit dose for oral and pulmonary administration.

The present invention is also directed to mouthpieces adapted to fitonto a drug delivery device for administering a drug in multiparticulateform into the oral cavity of a patient, the improvement being that themouthpiece protrudes from the drug delivery device at an angle in orderto direct the multiparticulates onto the tongue of the patient.

The present invention is also directed to mouthpieces which are conicalor rectangular in shape and which provide a flared opening, wherein thearea of the outlet of the mouthpiece is larger than the area of theinlet of the mouthpiece. This reduces the velocity of the deliveredmultiparticulates in order to minimize pulmonary deposition.

The present invention is also directed to mouthpieces and devices whichdrop the unit dose vertically onto the tongue with minimal or nohorizontal velocity. This action directs the unit dose down to thetongue and minimizes movement of particles toward the back of the throatin order to minimize or avoid pulmonary deposition. In preferredembodiments, when the device is utilized as intended, greater than 80%of the unit dose is administered from the device in a downward directionfrom about 45 degrees to about 135 degrees based on a vertical baselineindependent of the device. Preferably greater than 90% of the drugfollows this direction.

The invention is also directed to methods of providing a therapeuticeffect to a patient comprising administering to the patient a unit doseof a drug utilizing the systems, devices and formulations disclosedherein. The invention is also directed to methods of preparing thesystems, devices and formulations disclosed herein.

The invention is also directed to novel powders for oral administrationwhich are disclosed herein.

For purposes of the present invention, the term “device” refers to anapparatus capable of delivering a unit dose of drug.

The term “system” refers to a drug delivery device in combination withthe disclosed multiparticulate drug having the specifications disclosedherein, e.g. drug particle size, excipient type, etc.

The term “discreet collection” refers to a non-compressed free flowingunit of multiparticulates with minimal particulate matter beingdispersed in the surrounding environment (e.g., as a cloud or mist).

The term “drug” refers to any agent which is capable of providing atherapeutic effect to a patient upon gastrointestinal deposition. Thisencompasses all drugs which are intended for absorption for a systemiceffect (regardless of their actual bioavailability) as well as drugsintended for a local effect in the gut and/or oral cavity, e.g.nystatin, antibiotics or local anesthetics.

The term “particle size” refers to the diameter of the particle.

The term “deposition” means the deposit of the unit dose at the intendedpoint of absorption and/or action. For example, gastrointestinaldeposition means the intended deposit of the unit dose in thegastrointestinal system for e.g., absorption for a systemic effect or toexert a local effect. Pulmonary deposition means the intended deposit ofdrug into the lungs in order to provide a pharmaceutical effect,regardless that the unit dose may enter the oral cavity prior topulmonary deposition.

The term “dispense”, when used in connection with the devices andsystems of the present invention, means that the device or systemdelivers the unit dose ex vivo with the intent of subsequentadministration to a mammal. For example, the device or system candispense the unit dose into a food, a liquid, a spoon, or anotherintermediate receptacle.

The term “administer”, when used in connection with the devices andsystems of the present invention, means that the device or systemdelivers the unit dose in vivo, i.e., directly into the gastrointestinaltract of a mammal.

The term “deliver” is meant to cover all ex vivo and in vivo delivery,i.e.; dispensing and administering, respectively.

The term “patient” refers to humans as well as other mammals in need ofa therapeutic agent, e.g., household pets or livestock. This term alsorefers to humans or mammals in need of or receiving prophylactictreatment.

In certain embodiments, the particulates are defined functionally withrespect to the fact that they are of a size such that an effective dosecannot be delivered into the lower lung of a human patient. However,this definition should be understood to mean that a small percentage ofdrug (but not an amount effective to render a therapeutic effect) may infact be inadvertently delivered to the lungs of the patient. Also, thisdefinition is meant to define the particles, but not to limit the use ofthe invention to the treatments of humans only. The invention may beused for delivering doses of drugs to other mammals as well.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic side view of a delivery device according to theinvention in an upright position; and

FIG. 2 is a schematic side view of the device of FIG. 1 in the inverted(delivery) position.

FIG. 3 is a vertical section through another form of delivery deviceaccording to the invention having a mouthpiece;

FIG. 4 is a front view of the device of FIG. 3, with the mouthpiecefolded into a storage position;

FIG. 5 is a vertical section through a third form of delivery deviceaccording to the invention, having a mouthpiece;

FIG. 6 is a front view of the device of FIG. 5 with the mouthpiecefolded into a storage position; and

FIG. 7 is a vertical section through a fourth form of delivery deviceaccording to the invention.

FIG. 8 is an illustration of an embodiment of the invention comprising adrum reservoir.

FIG. 9 is an illustration of an embodiment of the invention having arotatable member outside of the reservoir.

FIG. 10 is an illustration of is an illustration of an embodiment of theinvention having a rotatable wheel outside of the reservoir.

FIG. 11 is an illustration of an embodiment of the invention having arotatable plate mechanism.

FIG. 12 is an illustration of an embodiment of the invention having aslidable plate mechanism.

FIG. 13 is an illustration of an embodiment of the invention having anarchimedean screw.

FIG. 14 is an illustration of an embodiment of the invention having aslidable member mechanism.

FIG. 15 is an illustration of an embodiment of the invention having aslidable reservoir mechanism.

FIG. 16 is an illustration of an embodiment of the invention having apull cord mechanism.

FIG. 17 is an illustration of a blister pack.

FIG. 18 is an illustration of an opening mechanism for a blister stripor roll

FIG. 19 is an illustration of a piercing mechanism for a blister stripor roll.

FIGS. 20 and 20A are illustrations of circular blister packs.

FIG. 21 is an illustration of a powder delivery device comprising alifting rod.

FIG. 22 is an illustration of a powder delivery device with anoptionally coupled powder feeder.

FIG. 23 is an illustration of a powder delivery device with an internalreservoir.

FIG. 24 is an illustration of an angled mouthpiece.

FIG. 25 is an illustration of a curved mouthpiece.

FIG. 26 is an illustration of a straight angled mouthpiece.

FIG. 27 is an illustration of a conical mouthpiece.

FIG. 28 is an illustration of a rectangular mouthpiece.

FIG. 29 is an illustration of a fanlike rectangular mouthpiece.

DETAILED DESCRIPTION

In general, it has been recognized in the art that dry powder inhalationor insufflation formulations must consist of particles of a size ofabout 2 microns in diameter in order for the particles, when inhaled, toreach the peripheral or “deep” lung, including alveoli. Particles largerthan 10 microns in diameter are not able to reach the deep lung wheninhaled because they are collected on the back of the throat and upperairways in humans. Therefore, known powder delivery systems have beenformulated with particle sizes of less than 10 microns in order for theparticles to reach the intended site of action, the pulmonary system.Known powder delivery devices have not contemplated delivery ofparticles from a multi-dose delivery device to achieve gastrointestinaldeposition, and therefore have avoided the use of drug particles havinga large size, e.g. greater than 10 microns. By virtue of the presentinvention, it has been a surprising discovery that drug particlesgreater than 10 microns can be delivered from a multi-use drug deliverydevice for gastrointestinal deposition in a patient in order to minimizethe inhalation of the drug particles into the lungs, in order to havesubstantially all of the dose deposited in the gastrointestinal system.

The present invention is directed to a system comprising a devicecontaining multiple doses of a drug which is in multiparticulate form.When the system is actuated, the device delivers a unit dose, preferablyby administration into the oral cavity of a patient, for the unit doseto be deposited in the gastrointestinal system of the patient forsubsequent absorption and/or action. Preferably, the unit dose issubsequently swallowed by the patient for absorption and/or action inthe stomach and/or intestines. However, the system can be used todeliver a unit dose of drug intended for sublingual or buccal absorptionand/or action.

In order to increase gastrointestinal deposition and reduce pulmonarydeposition, the unit dose is preferably administered as a discreetcollection. Administration of the unit dose as a discreet collectionensures that the multiparticulates are aggregated together and there isno dispersion or “mist” which forms in the oral cavity which would tendto be aspirated into the lungs.

The mean drug particle size of the unit dose is greater than 10 μm andpreferably greater than about 50 μm in order to minimize pulmonaryaspiration of the drug such that an effective dose of said drug cannotbe delivered into the lower lung of a human patient. For example, thedrug particles can be greater than about 75 μm, or greater than about100 μm. A preferred range of the mean drug particle size is about 100 μmto about 500 μm, although drug particles of 1 mm and above would stillbe functional in the present invention. Preferably, any inactiveparticle in the unit dose is also greater than 10 μm in order tominimize pulmonary aspiration of such particles.

In order to achieve the desired mean particle size, the active materialcan be incorporated into larger particles if the active agent itself isless than 10 μm. This can be performed by known procedures in the art,e.g., by granulation, coating, agglomeration or spray coating. Thelarger particles may include excipients suitable for use inpharmaceutical formulations.

The present invention is also directed to systems which contain drugparticles greater than 10 μm and drug particles of less than 10 μm ofthe same or a different drug which upon actuation, administer a unitdose for oral and pulmonary administration. For example, whengastrointestinal deposition is desired the drug will formulated, e.g.,to have at least 95% by weight of the gastrointestinal dose being ofaerodynamic diameter of at least 50 μm. For the inhalable dose, the drugwill be in the form of multiparticulates of which at least 90% by weightof the inhalable dose has an aerodynamic diameter of not more than 10μm. These particles can be arranged as to be releasable from largercarrier particles.

The gastric dose and the inhalable dose can be incorporated into asingle formulation comprising carrier particles; the inhalable drugbeing on the surface of the carrier particles and releasable therefromon inhalation from the device; and the larger particles being forgastrointestinal deposition. The two doses can be contained in the samereservoir or can be contained separately and co-administered uponactuation.

In preferred embodiments of the invention, the mean drug particle sizeof the multiparticulates does not vary by more than about 20%, morepreferably no more than about 15% and most preferably by no more thanabout 10%. Preferably, any inactive particles will also be within thisrange.

In preferred embodiments, greater than about 80% of the drug particlesfall within the above disclosed variance, more preferably greater than90% and most preferably about 100% of the drug particles fall within theabove disclosed ranges. For example, in a preferred embodiment, about90% of the drug particles of the unit dose would have a mean particlesize of about 450 to about 550 μm, although this example is not meant tobe limiting. Preferably, any inactive particles also fall within thisrange.

The size of the unit dose is dependent on the amount of drug needed toprovide the intended therapeutic effect and the amount of anypharmaceutically acceptable excipient which may be necessary. Typically,a unit dose of from about 0.01 mg to about 1.5 g would be sufficient tocontain a therapeutically effective amount of the drug to be delivered,however, this range is not limiting and can be smaller or higher,depending on the amount of drug and excipient that is necessary.Generally, the unit dose should not be so large that it is not capableof being swallowed by the patient without much difficulty. It ispreferred that the unit dose is of a small enough quantity that it canbe swallowed without the necessity of an additional liquid, however, theinvention is not limited to such quantity and doses which may require aliquid are contemplated by the invention. Preferably the unit dose isfrom about 1 mg to about 100 mg, or from about 10 mg to about 50 mg,depending on the potency of the active agent. In situations where theunit dose is too large to be easily swallowed, it is contemplated thatthe system can be actuated multiple times for subsequent delivery inorder to administer divided doses of the intended dose, which are moreeasily swallowed by the patient.

When it is contemplated for the unit dose to be swallowed without theuse of an additional liquid, certain embodiments of the inventionprovide that the multiparticulates comprise an effective amount of anagent which stimulates the production of saliva in order to facilitatethe swallowing of the unit dose. Such agents include any acid which issafe for human consumption and includes food acids, acid anhydrides andacid salts. Food acids include tartaric acid, malic acid, fumaric acid,adipic acid, and succinic acids and fruit-acids, e.g., citric acid. Acidanhydrides of the above described acids may also be used. Acid salts mayinclude sodium, dihydrogen phosphate, disodium dihydrogen pyrophosphate,acid citrate salts and sodium acid sulfite.

In other embodiments of the invention, the multiparticulates cancomprise an effervescent compound or composition which provides apleasing organoleptic effect which can substantially mask the taste ofunpalatable active ingredients in the powder. The effervescent actionalso acts as a stimulant to saliva production. Effervescent agentsinclude compounds which evolve gas. The preferred effervescent agentsevolve gas by means of chemical reactions which take place upon exposureto a liquid such as saliva in the mouth. This bubble or gas generatingchemical reaction is most often the result of the reaction of an acid(e.g. the saliva stimulant acids listed above) and an alkali metalcarbonate/dicarbonate or base. The reaction of these two general classesof compounds produces carbon dioxide gas upon contact with saliva.

The use of acids and/or effervescent ingredients is particularly usefulin patients with achlorhydria or other patients with a problemswallowing the unit dose without the use of a liquid.

For ease of swallowing and in order to minimize pulmonary aspiration ofmultiparticulates, the system preferably is configured to dispense theunit dose onto the tongue of the patient. The tongue can be stuck out inorder to facilitate the deposit of the unit dose thereon or preferably,the dispenser can be configured in order to deposit the unit dose on thetongue without the necessity of the patient sticking out the tongue.Preferably, the system is of such a configuration that the unit dose isdeposited behind the teeth towards the front of the tongue. The front ofthe tongue is preferred in order to stimulate the natural swallowing ofthe unit dose into the esophagus. This reduces the possibility of anyindividual particles becoming airborne and inhaled into the pulmonarysystem and facilitates the swallowing of the unit dose by initiating amore natural swallowing reflex. However, the unit dose should be able tobe placed anywhere on the tongue, including the deposit on the back ofthe tongue without stimulating the soft palate to cause a gag reflex.

As with most pharmaceutical formulations, it is often necessary to add apharmaceutically acceptable excipient to the drug. For example, whenformulating an agent into tablets or capsules, a bulking agent is usedin order to provide enough mass to tablet or capsule the agent. Thisresults in many of the drawbacks of solid dosage forms which werediscussed above.

With the present invention, however, it is not necessary to have a largepercent of the formulation consisting of excipient as it is preferableto have the unit dose which is deposited on the tongue of the patient assmall as possible in order to facilitate swallowing. The use ofexcipient is used in the present invention, e.g., to improveflowability, to taste mask, to stimulate flow of saliva for swallowingor to provided a modified release of the drug. In preferred embodimentsthe excipient is less than about 20% by weight of the multiparticulatesand more preferably less than about 10% by weight of themultiparticulates. These preferred percent weights of excipients are notmeant to be limiting. For example, with a micro-dose drug such asdigoxin or levothyroxine, the percent of excipient may need to be morethan 20% in order to provide enough bulk for acceptable flow or dosemetering characteristics.

The pharmaceutical acceptable excipient of the multiparticulates cancoat the drug. In such an embodiment, the excipient can provide amodified release of the drug. For example, such a multiparticulate canbe formulated to provide a delayed release wherein the drug is releasedin the intestine. Multiparticulate with an excipient coating can also beformulated in order to provide a sustained release of the drug over timein the gastrointestinal tract. Coating the drug with excipient can alsobe done in order to mask the bitter taste of certain drugs.

Alternatively, the excipient can be used as a substrate and the drug canbe coated onto the excipient. This formulation option can be used inorder to provide desired flow capabilities and to provide a criticalmass of the drug particles in order to minimize lung aspiration.

The excipient can also be used in a mixture with the in order to providethe desired properties (e.g., flow properties) to allow the unit dose tobe delivered as a discreet unit, with minimal multiparticulatessuspended in the air.

When the multiparticulates are formulated as controlled release powders,the drug may be combined with a polymer which may be soluble, insoluble,permeable, impermeable or biodegradable. The polymers may be polymers orcopolymers. The polymer may be a natural or synthetic polymer. Naturalpolymers include polypeptides, polysaccharides and alginic acid. Asuitable polypeptide is zein and a suitable polysaccharide is cellulose.The drug/polymer combination can be formed by known methods such asgranulating, spray coating or agglomerating.

Representative synthetic polymers include alkyl celluloses, hydroxyalkylcelluloses, cellulose ethers, cellulose esters, nitro celluloses,polymers of acrylic and methacrylic acids and esters thereof,polyamides, polycarbonates, polyalkylenes, polyalkylene glycols,polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols,polyvinyl ethers, polyvinyl esters, polyvinyl halides,polyvinylpyrrolidone, polyglycolides, polysiloxanes and polyurethanesand co-polymers thereof. The polymer to be used is governed by itstoxicity and its compatibility with the particular active ingredientbeing used and can be selected without difficulty by those skilled inthe art.

Particularly suitable polymers include: methyl cellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate(lower, medium or higher molecular weight), cellulose acetatepropionate, cellulose acetate butyrate, cellulose acetate phthalate,carboxymethyl cellulose, cellulose triacetate, cellulose sulphate sodiumsalt, poly(methyl methacrylate), poly(ethyl methacrylate),poly(butylmethacrylate), poly(isobutyl methacrylate),poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(laurylmethacrylate), poly(phenyl methacrylate), poly(methyl acrylate),poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecylacrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene)high density, poly(propylene), poly(ethylene glycol), poly(ethyleneoxide), poly(ethylene terephthalate), poly(vinyl alcohol), poly(vinylisobutyl ether), poly(vinyl acetate), poly(vinyl chloride) andpolyvinylpyrrolidone. Especially suitable co-polymers include: butylmethacrylate/isobutyl methacrylate co-polymer, high molecular weight,methylvinyl ether/maleic acid co-polymer, methylvinyl ether/maleic acid,monoethyl ester co-polymer, methylvinyl ether/maleic anhydrideco-polymer and vinyl alcohol/vinyl acetate co-polymer.

Representative biodegradable polymers include, polylactides,polyglycolides, poly(ethylene terephthalate), polyhydroxy-butyrate,polyhydroxy-valerate and polyurethane.

Representative acrylates and methacrylates are polyacrylic andmethacrylic polymers such as those sold under the Trademarks Eudragit.Amberlite and Carbopol.

Classes of drugs which are suitable in the present invention includeantacids, anti-inflammatory substances, coronary dilators, cerebraldilators, peripheral vasodilators, anti-infectives, psychotropics,anti-manics, stimulants, anti-histamines, laxatives, decongestants,vitamins, gastro-intestinal sedatives, anti-diariheal preparations,anti-anginal drugs, vasodilators, anti-arrhythmics, anti-hypertensivedrugs, vasoconstrictors and migraine treatments, anti-coagulants andanti-thrombotic drugs, analgesics, anti-pyretics, hypnotics, sedatives,anti-emetics, anti-nauseants, anti-convulsants, neuromuscular drugs,hyper- and hypoglycemic agents, thyroid and anti-thyroid preparations,diuretics, anti-spasmodics, uterine relaxants, mineral and nutritionaladditives, anti-obesity drugs, anabolic drugs, erythropoietic drugs,anti-asthmatics, bronchodilators, expectorants, cough suppressants,mucolytics, drugs affecting calcification and bone turnover andanti-uricemic drugs.

Specific drugs include gastro-intestinal sedatives such asmetoclopramide and propantheline bromide; antacids such as aluminumtrisilicate, aluminum hydroxide, ranitidine and cimetidine;anti-inflammatory drugs such as phenylbutazone, indomethacin, naproxen,ibuprofen, flurbiproferi, diclofenac, dexamethasone, prednisone andprednisolone; coronary vasodilator drugs such as glyceryl trinitrate,isosorbide dinitrate and pentaerythritol tetranitrate; peripheral andcerebral vasodilators such as soloctidilum, vincamine, naftidrofuryloxalate, co-dergocrine mesylate, cyclandelate, papaverine and nicotinicacid; anti-infective substances such as erythromycin stearate,cephalexin, nalidixic acid, tetracycline hydrochloride, ampicillin,flucloxacillin sodium, hexamine mandelate and hexamine hippurate;neuroleptic drugs such as flurazepam, diazepam, temazepam,amitryptyline, doxepin, lithium carbonate, lithium sulfate,chlorpromazine, thioridazine, trifluperazine, fluphenazine,piperothiazine, haloperidol, maprotiline hydrochloride, imipramine anddesmethylimipramine; central nervous stimulants such as methylphenidate,ephedrine, epinephrine, isoproterenol, amphetamine sulfate andamphetamine hydrochloride; antihistamic drugs such as diphenhydramine,diphenylpyraline, chlorpheniramine and brompheniramine; anti-diarrhealdrugs such as bisacodyl and magnesium hydroxide; the laxative drug,dioctyl sodium sulfosuccinate; nutritional supplements such as ascorbicacid, alpha tocopherol, thiamine and pyridoxine; anti-spasmodic drugssuch as dicyclomine and diphenoxylate; drugs affecting the rhythm of theheart such as verapamil, nifedipine, diltiazem, procainamide,disopyramide, bretylium tosylate, quinidine sulfate and quinidinegluconate; drugs used in the treatment of hypertension such aspropranolol hydrochloride, guanethidine monosulphate, methyldopa,oxprenolol hydrochloride, captopril and hydralazine; drugs used in thetreatment of migraine such as ergotamine; drugs affecting coagulabilityof blood such as epsilon aminocaproic acid and protamine sulfate;analgesic drugs such as acetylsalicylic acid, acetaminophen, codeinephosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate,oxycodeinone, morphine, heroin, nalbuphine, butorphanol tartrate,pentazocine hydrochloride, cyclazacine, pethidine, buprenorphine,scopolamine and mefenamic acid; anti-epileptic drugs such as phenytoinsodium and sodium valproate; neuromuscular drugs such as dantrolenesodium; substances used in the treatment of diabetes such astolbutamide, disbenase glucagon and insulin; drugs used in the treatmentof thyroid gland dysfunction such as triiodothyronine, thyroxine andpropylthiouracil, diuretic drugs such as furosemide, chlorthalidone,hydrochlorthiazide, spironolactone and triamterene; the uterine relaxantdrug ritodrine; appetite suppressants such as fenfluraminehydrochloride, phenternine and diethylproprion hydrochloride;anti-asthmatic and bronchodilator drugs such as aminophylline,theophylline, salbutamol, orciprenaline sulphate and terbutalinesulphate; expectorant drugs such as guaiphenesin; cough suppressantssuch as dextromethorphan and noscapine; mucolytic drugs such ascarbocisteine; anti-septics such as cetylpyridinium chloride,tyrothricin and chlorhexidine; decongestant drugs such asphenylpropanolamine and pseudoephedrine; hypnotic drugs such asdichloralphenazone and nitrazepam; anti-nauseant drugs such aspromethazine theoclate; haemopoietic drugs such as ferrous sulphate,folic acid and calcium gluconate; uricosuric drugs such assulphinpyrazone, allopurinol and probenecid; and calcification affectingagents such as biphosphonates, e.g., etidronate, pamidronate,alendronate, residronate, teludronate, clodronate and alondronate.

Drugs which possess taste and/or odor characteristics which, whenadministered orally without any excipients, render the drug ortherapeutic agent unpalatable to a subject and would be candidates fortaste masking in the present invention include, but are not limited to,H₂ receptor antagonists, antibiotics, analgesics, cardiovascular agents,peptides or proteins, hormones, anti-migraine agents, anti-coagulantagents, anti-emetic agents, anti-hypertensive agents, narcoticantagonists, chelating agents, anti-anginal agents, chemotherapy agents,sedatives, anti-neoplastics, prostaglandins, antidiuretic agents and thelike. Typical drugs include but are not limited to nizatidine,cimetidine, ranitidine, famotidine, roxatidine, etinidine, lupitidine,nifentidine, niperitone, sulfotidine, tuvatidine, zaltidine,erythomycin, penicillin, ampicillin, roxithromycin, clarithromycin,psylium, ciprofloxacin, theophylline, nifedipine, prednisone,prednisolone, ketoprofen, acetaninophen, ibuprofen, dexibuprofenlysinate, flurbiprofen, naproxen, codeine, morphine, sodium diclofenac,acetylsalicylic acid, caffeine, pseudoephedrine, phenylpropanolamine,diphenhydramine, chlorpheniramine, dextromethorphan, berberine,loperamide, mefenamic acid, flufenamic acid, astemizole, terfenadine,certirizine, phenytoin, guafenesin, N-acetylprocainamide HCl,pharmaceutically acceptable salts thereof and derivatives thereof.

Dry powder inhalation devices require high air flow to create shearconditions sufficient to isolate discrete drug particles in thepulmonary system. The greater the air flow, the more the devicedisperses the powdered drug into smaller, more respirable particles.This air flow is in the range of about 20 litres/min. to about 150litres/min. and results in high shear forces on agglomerates of drug andcauses collisions between the agglomerates of powdered drug both ofwhich tend to deagglomerate the large agglomerates into the desiredprimary particles for pulmonary deposition. In certain embodiments ofthe present invention, the air flow provided is enough to facilitate theunit dose of drug out of the device, but not-enough in order to projectthe particles into a “mist” for inhalation into the pulmonary system.This air flow is less than 20 litres/min, preferably less than about 10litres/min. In the present invention, devices from the prior art can bemodified in order to provide the desired less than 20 litres/min.airflow. In alternate embodiments, there is minimal air flow and thepowder dispenses from the device into the oral cavity throughgravitational force or mechanical action. In certain embodiments, theunit dose is metered and mechanically moved to the dispensing hole ofthe device (against or in the direction of gravity) prior to dispensing.

In certain embodiments, the multiparticulates are contained in areservoir. Preferably, the reservoir contains multiple doses of themultiparticulates in order to provide a multiplicity of unit doses. Thenumber of unit doses contained in the reservoir and capable of beingdelivered by the system depends on, among other factors, the frequencyof dosing and the duration of therapy of the drug being dispensed. Forexample, for acute therapy, the system can be configured to deliver 30unit doses of an antibiotic being prescribed three times daily for 10days. Alternatively for chronic therapy, the system can be configured tocontain 30, 100 or even 365 doses of an antihypertensive drugadministered once daily.

In certain embodiments, the system of the invention can be configuredwherein the reservoir is replaceable, e.g., in the form of a replaceablecartridge, or wherein the reservoir is capable of being refilled, e.g.,by including a removable plug wherein bulk powder can be introduced.However, in embodiments wherein the system is capable of being refilled,it is preferable that the system utilizes a replaceable system such asthe previously disclosed cartridge device rather than refilling thesystem with bulk powder through an unplugged hole as the latter may bemore prone to human error, e.g., loss of powder due to spilling orimproper manipulation. Further, the handling of bulk powders may resultin contamination of the reservoir, powder or both with moisture and/orcontaminants.

In other embodiments the system can be disposable, wherein afteradministration of all of the unit doses, the system is not capable ofbeing replaced with additional unit doses of the drug. This embodimentcan be beneficial for many reasons. Most prominently, a disposablesystem will give the patient, the prescriber and the manufacturer,greater assurances that the patient is receiving a proper dosage from afunctional system that has not been subjected to improper handlingand/or internal friction for a long duration of time. Such a disposabledevice may also reduce the overall cost of manufacture, as the devicewould only have to be manufactured to provide an accurate dose for afinite period of time. With refillable systems, greater care would haveto be taken in the manufacturing process and materials selected in orderto assure that the device is capable of providing an accurate dose for alonger period of time, e.g. over a year. As a compromise between thedisposable and refillable system, a refillable system can bemanufactured wherein the patient is informed that after a certain amountof time and/or courses of therapy, the system should be replaced with anew device. Such a system would be beneficial to the patient, prescriberand manufacturer by reducing manufacturing cost, improving patientconvenience by being able to refill the device and assuring to allparties that a patient will not be using a device which may benon-functional due to internal friction and/or improper handling.

In certain embodiments, a counter can be included in the system whichcan improve compliance of the patient. This is done by the count orindicator being utilized to know how many doses have been taken forthose patients who sometimes forget if they have taken a previous dose.With solid dosage forms, if a patient has forgotten if a previous dosehas been taken, it is often necessary to count the remaining doses tosee if one was taken. This creates problems such as contamination andalso the likelihood of miscounting wherein the patient might take adouble dose or skipped dose due to a counting error. The counter willalso keep the user apprised as to when the drug will run out and willhelp to improve proper planning for the patient to frequent a pharmacyin a timely manner. This can reduce the likelihood of a patient being“surprised” when the system does not provide any unit doses. The devicecan alternatively count the doses delivered by counting up, or can countdown to show the number of unit doses remaining in the system. Thecounter can be an electrical or mechanical mechanism which are commonlyknown in the art. The indicator can also be a visual mechanism, e.g.,the powder could fall below a colored marker which would indicate thenumber of doses remaining, the device can expose the internal powder toview in a window, or other mechanisms known in the art.

In the present invention, unlike tablets or capsules which have patientinstruction labels on secondary containers, the system of the presentinvention has a label permanently affixed to the container by themanufacturer, prescriber or dispenser. As the drug is not separated fromthe container, the label in not disassociated from the drug and thelabel can be seen at or between each dose.

In certain embodiments, the unit dose of multiparticulates is meteredout of the reservoir and expelled from the device. Preferably the unitdose exits the reservoir into a delivery conduit which transports theunit dose out of the device to the oral cavity of the patient or anintermediate receptacle. The delivery conduit can be in the form of ahollow tube, or a molded conduit with a hollow center wherein the unitdose can be transported. In certain embodiments, the unit dose passesthrough the deliver conduit into the oral cavity due to gravity whereinit is necessary to hold the unit in an upright position during actuationand delivery. However, it is contemplated in certain embodiments of theinvention that delivery out of the reservoir and throughout the conduitfor delivery of the unit dose can be facilitated by use of a gas oraqueous carrier. For example a gas can be released upon actuation tofacilitate the outward motion of the unit dose out of the device. Thegas can be pressurized and located in an additional reservoir in thesystem or it can be compressed in the same reservoir as themultiparticulates. The pressurized gas can be compressed air or liquidgas which becomes a gas upon release from the container. In anotherembodiment, a liquid can be released from a separate reservoir whereinthe multiparticulates and the liquid mix after actuation and a liquidsuspension of the multiparticulates is deposited into the oral cavity ofthe patient.

In preferred embodiments, the system administers the unit dose againstgravity by mechanical means. In such an embodiment, the reservoir orblister containing the unit dose is at a point below the mouth prior toadministration and upon actuation, the unit dose is moved againstgravity to the output cavity, where it is deposited onto the tongue. Atthe point of deposit, gravity may be used. This provides a morecomfortable and convenient motion for the patient, rather than thealternative where the unit dose is at a point higher than the oralcavity and is transported with, or assisted by gravity to the point ofoutput. For example, a sipping straw has a more comfortable andconvenient feel to a user when the contents are drawn up to the tongue,rather than drawn down from the point of origin, e.g., the reservoir.

It is also contemplated that the unit dose can be mechanically expelledfrom the device, e.g., by action of a plunger, auger or similarmechanism. This can be used in order to assure that all of the unit doseis expelled from the device. For example, if there is moisturecontamination at the point of expulsion, an amount of the unit dose maystick to the device. A plunger, auger or similar mechanism wouldminimize or remove this possible situation.

As previously disclosed, it is contemplated that the unit dose may insome circumstances be expelled not into the oral cavity, but into abeverage, food, holder (e.g., a spoon), or other suitable intermediatereceptacle prior to ingestion.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

With reference to FIG. 1, a delivery device 1 has a housing 2, whichincludes a base 3 and an outlet portion 4. Within the housing is achamber 5 of circular cross section. The chamber encloses a batch 6 of aparticulate pharmaceutical preparation, for example, a powder orgranular preparation, which comprises an orally active drug. At theupper extremity of chamber 5 is a delivery conduit 7 which communicateswith a delivery outlet 8. A cap 9 can cover the outlet 8, and may beattachable by friction fit or snap fit means (not shown in the drawings)to the circumferential surface of the housing 2. A metering device 10 isprovided at the periphery of the chamber 5 for the purpose of metering adose of the preparation from the chamber 5 and discharging the metereddose into the delivery conduit 7. The metering device, which is notshown in FIG. 1, may for example be of a kind used for metering drypowder formulations in dry powder inhalers. One suitable form of such ametering device is described in European Patent Specification No. 0 661071 B, the disclosure of which is incorporated herein by reference.

FIG. 2 shows the device of FIG. 1 in the inverted position. As a resultof inversion, the preparation is located immediately adjacent to, thedelivery conduit 7 and metering device 10. On actuation of the meteringdevice (in the case of devices such as that of EP 0 661 071B, byrotation), a dose of the preparation is metered and discharged intodelivery conduit 6, through which it falls under the influence ofgravity to delivery outlet 8. If desired, the dispersed dose may becollected in a receptacle 11.

In the use of rotatable metering devices such as those known in the artof dry powder inhalers, it is frequently necessary for the user toemploy both his or her hands to use the device, as a result of thetwisting action required to actuate the metering device. It is envisagedthat the device of the invention might be provided with a gearing meanscommunicating between the rotatable device and a remote actuation deviceon the device housing, the remote actuation device being arranged topermit actuation using the hand in which the device is held. The remoteactuation means may be, for example, operable by pressing or squeezingor a tab or button.

Referring to FIG. 3, in another form of device according to theinvention the drug may be delivered directly into the patient's mouth.The device of FIGS. 3 and 4 has an elongate housing 21, in which ismounted a shallow drum-shaped reservoir 22 containing the particulatematerial 23 to be dispensed. The axis of the reservoir 22 extendstransversely across the elongate housing and the reservoir 22 has adiameter that is greater than the width of the housing 21, so that theextremities of the reservoir extend beyond the sides of the housing. Thereservoir 22 is rotatable and may be arranged to meter the particulatematerial 23 in an analogous manner to that described above in relationto FIGS. 1 and 2. A delivery conduit 24 is provided in the housingunderneath the reservoir 22 to receive metered doses of materialtherefrom, for delivery to an opening 25. A mouthpiece 26 is positionedagainst the housing about the opening 25.

A pathway 27 defined within the mouthpiece 26 communicates with theopening 25 for receiving the particulate material therefrom. An airopening, with a valve (neither is shown) is provided in the housing 21and also so communicates with the delivery conduit 24 that air can bedrawn in through that air opening when a patient sucks through themouthpiece. The valve is so arranged that it permits only a limitedamount of air, in general less than 20 cm3, to be drawn in through theopening during a single sucking action of the patient, the valve closingafter that amount of air has passed to prevent further air being drawnin.

The mouthpiece 26 has an elongate portion 28 immediately adjacent to theopening 25. Extending from the elongate portion 28 at the distal endrelative to the housing 21 is a flared portion 29 which defines adownwardly facing delivery outlet 30. Underneath the elongate portion 28is provided a stop member 31 which serves to indicate to the user thecorrect depth of insertion into the mouth of the mouthpiece 26. Themouthpiece 26 is mounted on a pivot 32, about which the mouthpiece ispivotable from the working position to a storage position. The storageposition is indicated in FIG. 3 by broken lines. When the mouthpiece 26is in the storage position, the opening 25 at the outlet of the deliveryconduit 24 may be closed by means of a slidable closure plate 33, whichprotects against ingress of moisture into the reservoir 22 betweendispensing operations. On release of the mouthpiece 26 from the storageposition, actuation means (not shown) are operable to actuate thedispensing mechanism (including the reservoir 22) and a dose counter. InFIG. 4, the device is shown with the mouthpiece 26 in the storageposition.

The configuration and relative dimensions of the mouthpiece 26 of thedevice of FIGS. 3 and 4 are chosen so as to ensure that substantiallyall of the dispersed particulate material 23 is delivered to, anddeposited in, the patient's mouth. In particular, they are chosen withthe object of preventing accidental inhalation of material. Thus, theelongate portion 28 of the mouthpiece 26 defines a flow channel 27 a ofrelatively small cross-section (for example, of circular cross-sectionof diameter 5 mm), which at the distal end flares outwardly into adelivery outlet 30 at which the pathway 27 b is of much greatercross-section. Furthermore, the delivery outlet 30 is orienteddownwardly. The flaring of the distal portion of pathway 27 b tends tocause a deceleration of airborne material received from the channel 27a, and that deceleration in combination with the orientation of theoutlet 30 promotes the deposit of the material within the patient'smouth and especially on the tongue. In addition, as discussed furtherbelow, the particulate material will preferably be so formulated as tominimize the amount of material that will remain airborne onadministration, and thus to minimize inhalation.

The device 34 of FIGS. 5 and 6 is similar to that of FIGS. 3 and 4, andparts present in FIGS. 3 and 4 are designated by the same referencenumerals in FIGS. 5 and 6. In addition to the structures alreadydescribed in relation to FIGS. 3 and 4, the device of FIG. 5 contains anadditional reservoir 35 with associated metering means (not shown) andassociated delivery conduit 36. The delivery conduits 24 and 36communicate with the pathway 27 in the mouthpiece 26 for delivery ofparticulate material thereto from respective reservoirs 22 and 35. InFIG. 6, the device of FIG. 5 is shown with the mouthpiece 26 in thestorage position. The reservoir 35 will usually contain a particulatematerial 37 comprising an orally active drug that is different from theorally active drug in the particulate material 23, although it will beappreciated that, if desired, material 37 could contain the same orallyactive drug, for use as a reserve source or for use in a differentdosage. For example, one of the reservoirs may contain a glitazone drug,whilst the other might then contain a sulphonylurea. The choice offurther combinations is a matter of routine for those skilled in theart, having regard to the known activities of drugs and any relevantcontra-indications.

The device 38 of FIG. 7 is in some respects similar to the device 20 ofFIGS. 3 and 4, and parts present in FIGS. 3 and 4 are designated by thesame reference numerals in FIG. 7. In the case of the device 38,however, there is additionally present a reservoir 39 and metering means(not shown) for a second particulate material 40 comprising a drug forinhalation. The device has a delivery conduit 41, into which materialmetered from the reservoir 39 enters in use. The delivery conduitcommunicates with an inhalation airway 42, which is arranged to receivematerial from the conduit 41. The path from reservoir 22 via deliveryconduit 24 into mouthpiece 26 and the path from reservoir 39 viadelivery conduit 41 into airway 42 are independent of one another.Whereas, as described in relation to the device 20 of FIGS. 3 and 4, thedelivery conduit 24 communicates with an air opening having a valve thatlimits the intake of air, the delivery conduit 41 communicates with aseparate air opening in the housing which permits essentiallyunrestricted admission of air on inhalation of the patient via airway42. The device includes selection means (not shown), which are operableby the patient to select which of the materials 23 or 40 is to beadministered. According to the selection made by the patient, the airpath communicating with the delivery conduit of the non-selectedmaterial is closed.

In contrast to the flared outlet 30 of the mouthpiece 26, the airway 42of device 38 is of substantially constant, or even taperingcross-section and is inclined only slightly downwardly. As a result, theairflow in the airway 42 tends to flow at a relatively high velocity,and possibly even to be accelerated. That, in combination with theorientation of the outlet of the airway, tends to promote inhalation ofthe particulate material. Suitable combinations of particulate materialsfor use in the reservoirs 22 and 39 include those comprising any of theorally active drugs already mentioned above (in the case of reservoir22) and those comprising any drug that is suitable for administration byinhalation (in the case of reservoir 39), provided of course that theselected drugs are compatible in use. Drugs suitable for inhalation willinclude, but are not limited to, those for use in the treatment orprevention of respiratory disease.

The device of FIG. 7 is especially suitable for administration wherethere is a need for both a rapid response and for continuing action. Forexample, in the case of pain control, there is frequently a need forfast relief from pain on commencing treatment, with pain relief thenbeing maintained. A further potential area of use is the treatment ofrespiratory disease by means of an inhalable drug during the day, and bymeans of a slower-acting orally active drug for use at night.

In certain embodiments as demonstrated in FIG. 8, the system comprises adevice which comprises a drum 81 having an inner cavity 82 disposedtherein for containing the multiparticulates 83. The drum having anouter lining 84, a rotatable inner lining 85 disposed immediately withinthe outer lining and a stationary retaining strip 86 located immediatelywithin a portion of the inner lining. The outer lining has a dispensinghole 87 at a point behind the retaining strip to dispense the unit doseand the rotating inner lining has a filling hole 88 disposed therein.The rotating inner lining has a first position 89 where the filling holeis not adjacent to the retaining strip to allow a unit dose of themultiparticulates to be filled therein; and a second position 810 wheresaid filling hole is adjacent to the retaining strip and incommunication with the outer hole. Upon actuation, the inner lining ismoved from the first position to the second position and the unit doseis delivered from the reservoir to the dispensing hole and expelled fromthe device for delivery to the patient. In this embodiment, the drumwhich holds the multiparticulates can be spherical or cylindrical.

In another embodiment as demonstrated in FIG. 9, the system comprises adevice which comprises a reservoir 90 containing the multiparticulates91 which has an exit hole therein 92; a rotatable member 93 outside thereservoir having an external cavity 94 in communication with the exithole when the rotatable member is in a first position, to allow a unitdose of the multiparticulates to be filled therein; a stationaryretaining housing 95 immediately covering the rotating member, theretaining housing having a dispensing hole 96 disposed therein; therotatable member having a second position wherein the external cavity ofthe rotatable member is in communication with the dispensing holewherein upon actuation, the rotatable member is moved, from the firstposition to the second position whereby the unit dose is delivered fromthe reservoir to the dispensing hole and expelled from the device fordelivery to the patient.

In another embodiment as demonstrated in FIG. 10, the system comprises adevice which comprises a reservoir 101 to contain the multiparticulates102, the reservoir having an exit hole 103 therein; a rotatable member104 outside the reservoir having a plurality, of external cavities 105;a stationary retaining housing 106 immediately covering the rotatingmember, the retaining housing having a dispensing hole 107 disposedtherein; the rotatable member in position wherein one external cavity isin communication with the exit hole, to be filled with a unit dose ofthe multiparticulates and one external cavity is in communication withthe dispensing hole; the rotating member being rotatable to advance eachcavity to the exact position of the next adjacent cavity wherein a unitdose of the multiparticulates is delivered from the dispensing hole whena cavity containing a unit dose is advanced to be in communication withthe dispensing hole.

In another embodiment as demonstrated in FIG. 11, the system comprises adevice which comprises a reservoir 111 to contain the multiparticulates112, the reservoir having an exit hole 113 therein; a movable plate 114having a filling hole 115 disposed therein, the movable plate, having afirst position wherein the filling hole is in communication with theexit hole of the reservoir; a stationary retaining plate 116 immediatelyunder the movable plate to form a filling cavity with the filling hole,to be filled with a unit dose of multiparticulates when the movableplate is in the first position, the stationary retaining plate having adispensing hole 117; the movable plate having a second position whereinthe filling hole is in communication with the dispensing hole. Uponactuation, the moving plate moves from the first position to the secondposition and a unit dose is delivered from the reservoir to thedispensing hole, where it is expelled from the device and administeredto the patient. In an alternate embodiment, the device has a stationaryupper plate 118 immediately over the movable plate, the upper platehaving a hole therein in communication with the reservoir hole and thefilling hole in order to retain the unit dose in the cavity duringtransmission from the first to the second hole. In certain embodiments,as shown in FIG. 11, the movable plate 114 is circular and rotatablymoves from the first position to the second position. In otherembodiments as demonstrated in FIG. 12, the movable plate 114 isrectangular and slidably moves from the first position to the secondposition.

In another embodiment of the invention, the system comprises a devicecomprising an archimedean screw 131 capable of reciprocal movement todispense a unit dose of multiparticulates from the reservoir 132 to bedischarged from the device into the oral cavity of the patient.

In another embodiment of the invention as demonstrated in FIG. 14, thesystem comprises a device comprising a shaft 141 in communication with areservoir 142 and a delivery conduit 143 in communication with theshaft, wherein said device is capable of providing a unit dose of thedrug from the reservoir to the delivery conduit. In a certainembodiments, the device further comprises a slidable member 144 withinthe reservoir and the shaft, the slidable member having a filling cavity145 disposed therein, the slidable member having a first position withthe filling cavity located in the reservoir and a second position withthe filling cavity located in the shaft and in communication with thedelivery outlet. Upon actuation, the slidable member moves from thefirst position to the second position, and a unit dose of the drug isdischarged from the reservoir into the delivery conduit and subsequentlyinto the oral cavity of the patient. In preferred embodiments, amechanism, e.g. a spring, 146 returns the slidable member to the firstposition after release of the unit dose. In an alternate embodiment asdemonstrated in FIG. 15, the slidable member is the reservoir 147 whichis enclosed within a housing 148.

In another embodiment of the invention as demonstrated in FIG. 16, thesystem comprises a device comprising an elongated tube 161 having aninternal cord 162, the cord having a plurality of evenly spaced nodules163 which plug the tube to form a plurality of evenly spaced air pockets164 within the tube, each of which contains a unit dose of themultiparticulates 165; wherein upon actuation, the cord is pulled toexpose a single air pocket and the unit dose is dispensed from thesystem and subsequently dispensed to the oral cavity of the patient.

In certain embodiments of the invention, the unit doses are individuallymetered prior to actuation. FIG. 17 illustrates an embodiment comprisingunit doses contained in blisters 171 on a substrate base 172, eachblister containing a unit dose, the substrate base and the blisterscovered by a seal 173. In certain embodiments the blisters are alignedlinearly in the form of a strip, and in alternate embodiments, the stripis in the form of a roll

In certain embodiments of the system comprising premetered blisters asdemonstrated by FIG. 18, upon actuation, the blister strip or roll isadvanced by a gear mechanism 180, an amount of seal covering one blisteris taken up by a first take up roller 181 and an equal portion ofsubstrate base is taken up by a second take up roller 182, whereby aunit dose-of multiparticulates is expelled from the strip and dispensedfrom the system into the oral cavity of the patient. Preferably, pinchrollers 183 are utilized in order to straighten the substrate base tofacilitate the rolling and storage of the used blister substrate.

In other embodiments of the system comprising premetered blisters asdemonstrated by FIG. 19, the system further comprises a piercing member191, wherein the strip is advanced to have a blister aligned with thepiercing member wherein upon actuation, the piercing member penetratesthe blister and a unit dose of multiparticulates is expelled from thestrip and dispensed from the system into the oral cavity of the patient.

In embodiments of the system comprising premetered blisters, thesubstrate base is disk shaped with the blisters arraigned on theperiphery of the disk. The blisters being equidistant from each otherand from the center of the pack as demonstrated by FIG. 20, wherein uponactuation the substrate base rotates about its central axis andpositions a blister in alignment with a piercing member. The piercingmember penetrating the blister to expel the unit dose from the blisterto be dispensed from the system into the oral cavity of the patient. Inalternate embodiments, the blisters can be arranged as a matrix asdemonstrated by Fog. 20 a, which would require a more complex mechanismin order to advance the blisters to the piercing member, or vice versa.

Another embodiment of the invention as demonstrated in FIG. 21 isdirected to a device for depositing a unit dose of multiparticulatescomprising a drug to the tongue of a patient comprising a housing 211having an inner cavity 212 formed therein for containing multiple dosesof the multiparticulates 213, the housing having a tapered top end 214with an opening therein 215 and a tapered bottom end 216; a lifting rod217 fitted at a first position 218 within the tapered bottom end of thehousing which is movable to a second position 219 within the tapered topend of the housing, the lifting rod comprising an elongated cylinder 220with a top end 221 and an inner push rod 222 within the elongatedcylinder which terminates at a point below the top end of the cylinderto form a filling cavity 223 when the lifting rod is in the firstposition (b), the inner push rod movable to terminate at a point abovethe top end of the cylinder when the lifting rod is at the secondposition (d); wherein when the device is upright in the first position,the filling cavity is filled with a unit dose of the multiparticulatesand when the lifting rod is moved to the second position, the inner pushrod moves to a point above the top end of the cylinder and the unit doseof drug is expelled from the housing onto the tongue of the patient (f).This embodiment of the invention can further comprising an endcap 224covering the opening of the tapered top end or at least one shutter 225covering the opening of the tapered top end, wherein the at least oneshutter opens when the lifting rod is in the second position. Thisembodiment of the invention can further comprise an inner ridge 226 inthe opening of the tapered top end, the inner ridge configured to engageand stop the motion of the elongated cylinder and not the inner pushrod, allowing the inner push rod to terminate at a point above the topend of the cylinder to expel the unit dose. The placement of the innerpush rod in the elongated cylinder at the first position is preferablyadjustable in order to vary the volume of the filling cavity andindividualize the dose of the drug. Preferably, the top tapered end isof sufficient length to allow the dose to deposit onto the back of thetongue of the patient. In certain embodiments, the device can be loadedwith drug and cocked at a position between the first and second positionprior to actuation as demonstrated in (c).

Another embodiment of the invention as demonstrated by FIG. 22 isdirected to a device for depositing a drug onto the tongue of a patientcomprising an elongated housing 221 having an inner cavity 223, thehousing having an opening 224 connecting the inner cavity to outside ofthe housing, the housing adapted to fit within the oral cavity of ahuman patient with the opening facing the tongue of the patient; amovable member 225 within the inner cavity, the movable member having afilling aperture 226 capable of containing a dose of drug, the fillingaperture enclosed by the housing when the movable member is in a firstposition (e), the movable member capable of being positioned to a secondposition (f) wherein the filling aperture is in communication with thehousing opening to load the drug into the aperture or to discharge thedrug onto the tongue of the patient. In certain embodiments, the movablemember is horizontally slidable from the first position to the secondposition or is rotatable within the elongated housing and rotates fromthe first position to the second position (h, i). Preferably, theelongated housing is of sufficient length to allow the drug to depositon the back of the tongue of the patient. This embodiment can alsocomprise a powder feeder 227 coupled to the opening of the housing todeposit a unit dose of drug into the aperture when the movable member isin the second position, the powder feeder being completely removablefrom the housing in order to allow for the deposit of the dose onto thetongue of the patient. In preferred embodiments, the powder feeder isattached to the housing by a folding member (e.g. a hinge, spring,flexible strip or similar mechanism) which provides a closed positionand an open position. When the housing and the powder feeder are in theclosed position, the powder feeder is coupled to the opening of thehousing and is in position to deposit a unit dose of drug into thefilling aperture 226 with the movable member is in the second position.In the open position, the housing and the powder feeder are in a spatialrelationship which allows the housing to dispense the unit dose into themouth of the user without hindrance due to the presence of the powderfeeder. In order to reduce steps involved in dispensing the drug, thefolding action from the open position to the closed position, or viceversa, can actuate a step in the dispensing process. For example, theopening of the device could trigger the filling of the aperture and/orthe movement of the movable member from the second position to the firstposition. Alternatively, the opening of the device could trigger thefilling of the aperture, the movement of the movable member from thesecond position to the first position during the initial opening, andthe movement of the movable member back to the first position fordispensing, during the end of the opening action, when the subsequentdispensing is unhindered by the powder feeder. The powder feeder cancomprise any mechanism for metering powder, including any of the abovedisclosed reservoir systems, e.g., the powder feeder can comprise ahousing 228 forming an inner reservoir 229 to hold multiple doses of thedrug in powder form 230, a shaft 231 in communicating with the reservoirand a delivery outlet 232 in communication with the shaft, wherein thepowder feeder is capable of providing a unit dose of the drug from thereservoir to the delivery outlet. In one embodiment, the powder feederfurther comprises a slidable member 233 within the inner reservoir andthe shaft having a filling cavity 234 disposed therein, the slidablemember having a first position 235 with the filling cavity located inthe reservoir and a second position 236 with the filling cavity locatedin the shaft and in communication with the delivery outlet, wherein uponmovement of the slidable member from the first position to the secondposition, a unit dose of the drug is discharged from the powder feederinto the filling aperture of the movable member.

Another embodiment of the invention as demonstrated by FIG. 23 isdirected to a device for depositing a drug onto the tongue of a patientcomprising a housing 231 forming a reservoir 232 and a shaft 233 incommunication with the reservoir, the housing having an opening 234connecting the shaft to outside of the housing, the housing adapted tofit within the oral cavity of a human patient with the opening facingthe tongue of the patient; a movable member 235 having a fillingaperture 236 capable of containing a dose of drug, the movable memberfitted within the shaft in a first position (b) wherein the fillingaperture is in communication with the reservoir and capable of beingfilled with the dose, the movable member capable of being positioned toa second position (d) with the filling aperture in communication withthe housing opening wherein the dose of drug is discharged onto thetongue of the patient. In certain embodiments the movable member ishorizontally slidable from the first position to the second position oris rotatable within the elongated housing and rotates from the firstposition to the second position. The device can further comprise alocking mechanism 237 to keep the position of the filling aperture at alocation between the first and second position (c). Preferably, thedevice comprises a mechanism, e.g. a spring 238, to position the movablemember to the second position upon release of the locking mechanism.Preferably, the top tapered end is of sufficient length to allow thedose to deposit onto the back of the tongue of the patient and has aremovable cap 239.

The systems and device of the present invention should contain thepowder in order to prevent contamination from the outside environment aswell as to assure a closure to prevent loss and waste of powder. Thiscan be accomplished by elastomeric sealing gaskets which can provide aseal between the reservoir and the other components to prevent leakageor escape of powder from the reservoir. Alternatively, this can beaccomplished by biasing the components with, e.g. a screw, in order toprovide tight frictional engagement between the drug containingcomponents.

Another aspect of the invention is directed to novel mouthpieces whichaid in the coordination of the unit dose into the oral cavity.

In certain embodiments, the mouthpiece initially protrudes from thedevice in a similar manner as a traditional mouthpiece on a standardinhaler. However, after the initial protrusion, the mouthpiece anglesdownward in order to direct the unit dose onto the tongue of the user asshown in FIG. 24. This is to assure that as close to 100% as possible ofthe unit dose is subsequently absorbed by the gastrointestinal tract andnot inhaled into the pulmonary system. The angled mouthpiece can have asharp angle (FIG. 24) or can be curved as shown in FIG. 25.

In another embodiment, rather than having the angled or curvedmouthpiece, the mouthpiece can be straight, but can protrude from thedevice, when the device is in an upright position at an angle (FIG. 26)in order to direct the unit dose onto the tongue and also to reduce anydeflection in the mouthpiece from the angle and curved mouthpiece whichmay result in some drug being retained and not delivered by the system.

Another novel feature of the mouthpiece of the present invention is tohave a flared mouthpiece which reduces the velocity of themultiparticulates and prevents the scattering and dispersion of the dosewhich may lead to pulmonary infiltration. In the prior art, narrowed orventuri style mouthpieces result in an increased velocity duringdelivery which is beneficial for pulmonary inhalation. By virtue of theflared mouthpiece of the present invention, the velocity of themultiparticulates is not increased, thereby increasing the percent ofdrug deposited gastrointestinally. As shown in FIG. 27, the flaredmouthpiece can be conical in shape 270, wherein diameter of the outletof the mouthpiece 271 is large than the internal entrance 272 whereinthe unit enters the mouthpiece. In preferred embodiments, the outletdiameter is 25%, 50% or 100% greater than the inlet diameter of themouthpiece. However these percentages are not meant to be limiting.

In other embodiments as demonstrated in FIG. 28, the mouthpiece can berectangular 281, with the horizontal top 282 and bottom 283 being longerthan the sides 284 in order to fit within the mouth of a patient.Similarly to the conical mouthpiece the outlet of the opening 285 willbe greater than the inlet opening 286. For example, the surface area ofthe outlet opening van be 25%, 50% or 100% larger than the inletopening.

In other embodiments with a rectangular style mouthpiece as depicted inFIG. 29, the outward protrusion of the mouthpiece 291 can be fanlike. Insuch an embodiment the side walls 292 of the mouthpiece extend outwardfrom the beginning of the mouthpiece 293 as angles, e.g. 15 degrees,going in opposite direction from each other to provide the flare. Whenthe walls reach the desired distance, the top and bottom of themouthpiece 294 are convex on their outer edges 295 in order to providethe fanlike appearance.

In certain embodiments of the invention, drug delivery devices known inthe art, e.g., powder inhaler art, can be modified/adapted in order tohave the capacity and the capability to actuate a unit dose of particleshaving a size suitable for gastrointestinal delivery with minimalinhalation into the pulmonary system. Such devices are described in theabove mentioned WO 94/04133, U.S. Pat. No. 4,590,206 and WO 93/25198,hereby incorporated by reference,. Other devices are described below:

One such device is known as the Bespak device described in PCTpublication WO 92/00771, hereby incorporated by reference, availablefrom Innovata Biomed Limited. The device described therein includes astorage chamber for storing a powdered drug to be administered and ametering member having metering cups in which individual doses of thepowdered drug are placed. Air is inhaled through an inhalation passageat one end of the device and directed into contact with the metering cupthat has been filled with the powdered drug. The metering cup isoriented upwardly open to face the air stream and to enable the powderto be released from the cup. Upon inhalation, the dose is mixed with theair flow and continues through the mouthpiece to be inhaled. Themetering cups on the metering member are arranged on an outerfrusto-conical wall so that each metering cup is positioned to beupwardly open and face the air flow during inhalation. The meteringmember rotates so that the metering cups move between a position inwhich the cup receives a dose of the powered drug from the storagechamber to a position in which the cup is exposed to the air flow. Asone cup is exposed to the air flow, another cup is aligned with thestorage chamber and is being filled with powder. After the dose is blownfrom the metering cup, and upon subsequent rotation of the meteringmember, the cup is wiped and cleaned by a wiping element to remove anyundispersed powder and then dried via a moisture absorbent material.

Another device for delivery of inhalation powders is described in U.S.Pat. No. 2,587,215 (Priestly), hereby incorporated by reference.Priestly describes an inhaler having a storage chamber containing apowdered drug, a mixing chamber and means to move a set dose of drugfrom the storage chamber to the mixing chamber. The dose is mixed withair in the mixing chamber and inhaled through a mouthpiece.

Yet another inhalation device suitable for delivering powderedinhalation drugs is described in U.S. Pat. No. 4,274,403 (Struve),hereby incorporated by reference. Struve describes an inhaler foradministering a powdered drug nasally, which includes storage means forcontaining a quantity of the drug therein. The storage means includes afeed hole through which the powdered drug may be received from thestorage means. The device further includes a dispensing head operativelycoupled to the storage means for dispensing the powdered drug morenasally. The dispensing head of the Struve inhaler includes a nozzle, abody portion, a dispensing cylinder and a vent means. The nozzle isshaped to be received in the nasal passage of the user. The nozzleincludes a dispensing passageway for dispensing the dose into the nasalcavity of patient. The body portion is located adjacent the nozzle andhas a traverse bore therein. The traverse bore operatively connects thedispensing passageway in the nozzle with the feed hole leading to thedrug storage means. The feed hole and the dispensing passageway aretransversely offset relative to one another at the points where theyenter the transverse bore.

The dispensing cylinder includes a metering chamber. The meteringchamber may be selectively aligned with either the feed hole or thedispensing passageway. The dispensing cylinder is slidably received inthe transverse bore for movement between a first transverse position inwhich the metering chamber is aligned with the feed hole and a secondtransverse position in which the metering chamber is aligned with thedispensing passageway. In its first position, the metering chamber canbe filled with a charge of the powdered drug when the inhaler ismanipulated. In the second position, places the charge of the powdereddrug into the dispensing passageway for inhalation by the user. The ventmeans is formed as part of the dispensing cylinder and is capable ofventing the metering chamber to atmosphere only in the second positionof the cylinder, i.e. when the powder disposed in the device such thatit may be inhaled by the user.

Another inhaler device is disclosed in U.S. Pat. No. 4,524,769(Wetterlin), hereby incorporated by reference. Wetterlin describes adosage inhaler for administering a micronized pharmacologically activesubstance to a patient. The inhaler includes a gas conduit means throughwhich gas passes for carrying the micronized substance to beadministered. The inhaler further includes a membrane having a pluralityof preselected perforated portions, each portion adapted to hold anddispense a reproducible unit dose of less than 50 mg of said activesubstance, in dry powder form. The powder particles have a particle sizeof less than 5 micrometers. The membrane is movably connected to the gasconduit means so that one of the preselected portions can be positionedwithin the gas conduit means so that the substance held in thepreselected portion may be dispensed. The remaining preselected portioncan be in a position external to said gas conduit means to receive saidactive substance. The membrane is movable through a plurality ofpositions whereby each preselected portion of the membrane can besuccessively positioned within the gas conduit to dispense the unit doseof the active substance held therein. Each preselected portion fromwhich the active substance has been dispensed can be moved to saidexternal position to receive active substance.

GB Patent Application No. 2,041,763, hereby incorporated by reference,describes an inhaler having a powder storage chamber and a rotatablemetering member having dosing holes which open to the storage chamber inone position and open to the mixing chamber in another position. Uponrotation of the metering member, the powder is carried from the storagechamber to the mixing chamber to be inhaled.

EP 0 079 478, hereby incorporated by reference, describes an inhalerhaving a storage chamber, inhalation air passage and rotatable deliverymember having a cavity formed therein. The delivery member is rotatedfrom one position in which the cavity receives powder from the storagechamber to another position in which the powder falls from the cavity bythe effect of gravity into a collector positioned in the air passage.

U.S. Pat. No. 4,860,740 (Kirk et al.), hereby incorporated by reference,describes an inhaler having a rotatable metering member with recessesformed therein. The recesses contain a powdered drug. Upon rotation ofthe metering member, one of the recesses in exposed to the airinhalation passage to be entrained in the air stream and inhaled.

The Easyhaler.TM., described in PCT publication WO 92/09322, herebyincorporated by reference, available from Boehringer Ingelheim isillustrative of another suitable device which can be adapted/modifiedfor delivering the formulations of the present invention. The deviceincludes a supply of a pulverized medical substance and a “dosingmeans”, which is a rotatable cylinder having five uniform recessesarranged around the periphery of the cylinder. The cylinder is rotatedsuch that one recess aligns with the supply of drug and is filled by aquantity of the drug while another recess aligns with an air channelconnected to the mouthpiece. The filled recess is then rotated toanother position in the direct path of an inhalation air flow. The doseis pre-set by the recessed portion of the rotatable dosing means and isflushed clean by the direct air flow through the inhalation chamber. Tooperate the device, the rotating dosing means is turned so that a fulldosing chamber (having already been filled up after the previous use) isrotated into alignment with the air channel leading to the mouthpiece.Upon inhalation by the user, air is drawn through apertures and nozzlesdirectly into the dosing chamber. The air flow flushes the dosingchamber causing the drug to be carried with the air in the direction ofthe inhalation through the mouthpiece. The axis of the air channel isarranged at an angle to the axis of the dosing means of between70.degree. and 110.degree., but preferably 90.degree. (perpendicular).

U.S. Pat. No. 5,176,132, hereby incorporated by reference, discloses adevice for the administration to the lung by inhalation of a drug inpowdered form. The device includes a mouthpiece, a drug reservoircommunicating with said mouthpiece, and metering means for dispensing adose of drug from the reservoir. The reservoir contains a compacted bodyof powdered drug including an active ingredient having a particle sizeof from 1 to 10 μm when in loose powder form. The metering meansincludes a rotatable helical blade for abrading the compacted body. Thuswhen actuated, the helical blade abrades the compacted powdered druginto particles capable of being inhaled into the respiratory tract of apatient.

International patent applications, PCT/EP93/01157 and PCT/EP93/01158(assigned to GGU), hereby incorporated by reference, are directed to aninhalation device and to a annular tablet, respectively. GGU's deviceincludes a drug reservoir body situated in a mouthpiece. The body formsthe beginning of an inhalation tube through which the drug is inhaled.The drug is in a compacted and annular (ring) form. In use, a face millcutter rotates, generating particles of the drug. Upon inhalation, airflows through air inlet openings in the casing and in the area of thecutting edges of the face mill cutter. Together with depressionssituated between the cutting edges, the inlet openings and thedepressions form an air channel leading to the mouthpiece, through whichthe drug particles are inhaled.

The quantity of each dose is determined by the amount of rotations ofthe face mill cutter. A spring presses the inhalation tube and thus thedrug body toward the face mill cutter. In operation, a wind-up button isrotated to load the spring. By pressing the trigger mechanism, thespring is released thereby rotating the upper portion to which isconnected the face mill cutter.

Other representative inhalers for medications are those described in,for example, U.S. Pat. Nos. 3,157,179; 3,178,748; 3,183,907; 3,356,088;3,361,306; 3,456,644; 3,456,646; 3,565,070; 3,656,070; 3,636,949;3,658,059; 3,732,864; 3,789,843; 3,814,297; 3,991,761; 3,826,413;4,206,758; 4,414,972; 4,484,577; 4,534,345; 4,592,348; 4,817,822;4,484,577; 4,926,852; 4,790,305; 4,210,155; 4,852,561; 4,644,107;4,677,975; 4,803,978; 4,934,358; 4,955,371; 5,020,527; 5,048,514;5,060,643; 5,224,471; 5,250,287; 5,284,133; and 5,351,683.Representative of nasal-pharyngeal inhalers for large mammals such as ahorse is that described in U.S. Pat. No. 5,062,423.

Representative devices for handling powder forms of medicine are shownand described in several U.S. Patents, including U.S. Pat. Nos.6,142,146; 6,116,238; 6,073,818; 6,071,498; 6,065,471; 6,029,663;6,006,747; 5,934,273; 5,875,776; 5,871,010; 5,785,049; 5,577,497;5,694,920; 5,642,728; 5,568,807; 5,546,932; 5,524,613; 5,476,093;5,447,151; 5,383,850; 5,372,128; 5,301,666; 5,287,850; 5,263,475;5,042,472; 4,889,114; 4,860,740; 4,846,168; 4,338,931; 5,458,1351;5,388,572; 5,349,947; 5,042,472; 3,507,277; 3,518,992; 3,635,219;3,831,606; 3,948,264; 3,971,377; and 4,147,166. Dry powder inhalersinclude dose inhalers, for example the single dose inhaler known by thetrade mark Monohaler® and multi-dose inhalers, for example a multi-dose,breath-actuated dry powder inhaler such as the inhaler known by thetrade mark Turbohaler®. Many of these prior art devices use powderedmedicine contained in a gelatin capsule or blister with a separate dosecontained in each capsule or blister. For example, in U.S. Pat. Nos.3,507,277; 3,518,992; 3,635,219; 3,795,244; and 3,807,400, inhalationdevices are described having means for piercing of a capsule containinga powdered drug, which upon inhalation is drawn out of the piercedcapsule and into the user's mouth. In U.S. Pat. No. 2,517,482, a deviceis described having a powder containing capsule placed in a lowerchamber before inhalation, where it is pierced by manual depression of apiercing pin by the user. After piercing, inhalation is begun and thecapsule is drawn into an upper chamber of the device where it movesabout in all directions to cause a dispensing of powder through thepierced holes and into the inhaled air stream. One well known dry powderinhaler, the Diskhaler, described in U.S. Pat. No. 4,627,432, usesindividual drug doses sealed within blisters on a blister disk. Aplunger pierces the blisters, to release each dose. The disk is advancedby a knob with each successive dose. The Spiros inhaler, described inU.S. patent application Ser. No. 08/681,103 is a dry powder inhalerwhich also uses a blister disk. Another inhaler described in PCTapplication No. PCT/US93/09751 contains individual medicine doses storedwithin a plurality of apertures in a medicine containing cartridge. Thecartridge is manually advanced to successive doses by rotating themedicine containing cartridge. U.S. Pat. Nos. 5,327,883, and 5,577,497,describe an inhaler having a spinning impeller.

Known devices for delivering aerosol medication for inhalation by apatient include metered dose inhalers that are manually operated andbreath actuated. Some Examples of devices for delivering aerosolmedication for inhalation are described in U.S. Pat. Nos. 5,960,792;5,848,587; 5,738,087; 5,666,948; 5,617,844; 5,505,194; 5,394,866;5290,539; 5,165,391; 5,027,806; 4,955,371; 4,852,561; 4,790,305;4,509,515; 5,954,047; 5,755,218; 5,724,986; 5,622,162; 5,544,647;5,505,194; 5,392,768; 5,304,125; 4,852,561; 3,187,748; 3,565,070;3,814,297; 3,826,413; 4,592,348; 4,648,393; 4,803,978; 4,896,832; aproduct available from 3M Healthcare known as Aerosol Sheathed Actuatorand Cap; and a product available from Raker Laboratories known asAutohaler.

Some Examples of fixed aerosol actuator devices of one-piececonstruction are described in U.S. Pat. Nos. 3,918,451; 3,991,761;4,011,864; 4,069,819; 4,227,522; 4,265,236; 4,454,877; 4,576,157;4,648,393; 4,860,740; 5,002,048; 5,012,804; 5,115,803; 5,134,993;5,134,993; 5,161,524; and 5,178,138.

Devices which are articulated and which can be folded or telescoped forconvenient carrying in a pocket or purse are described in U.S. Pat. Nos.3,739,950; 3,788,316; 3,927,806; 3,994,421; 4,130,116; 4,292,966;4,509,515; 4,637,528; and 4,641,644.

Breath activated inhalers differ from pressurized aerosol inhalers inthat breath activated inhalers are activated by inhalation of the userso that the drug is reliably drawn into the distal regions of the lung.Typical breath activated inhalers are described in U.S. Pat. Nos.6,102,036; 5,483,954; 4,846,168; 4,524,769. Other systems also include ameans of triggering the medication release by the start of inhalation.Such devices have been described in U.S. Pat. Nos. 4,664,107; 4,803,978and 4,739,754.

Some disposable, breath-actuated inhalers are described in WO 89/01348,U.S. Pat. No. 4,265,236. Other disposable inhalers are described in U.S.Pat. Nos. 6,102,035, 6,062,213, 5,660,169, 5,533,505, 4,955,371.

Other more recent improvements in inhalers are described in U.S. Pat.Nos. 6,149,892; 6,143,277; 6,131,566; 6,116,234; 6,062,213; 6,083,514;6,074,668; and 5,878,917.

All of the disclosures of these aforementioned patents are herebyincorporated by reference in their entireties.

1. A drug delivery system for gastrointestinal deposition, comprising amultiple unit dosing device comprising a housing and an actuator, saiddevice containing multiple doses of multiparticulates comprising drugparticles, said device upon actuation delivering a unit dose of saidmultiparticulates, said drug particles having a mean diameter of greaterthan about 50 μm to about 1 mm such that an effective dose of said drugcannot be delivered into the lower lung of a human patient.
 2. Thesystem of claim 1 wherein said delivery is by administering in vivo saidunit dose into the oral cavity of said patient.
 3. The system of claim 1wherein said delivery is by dispensing ex vivo said unit dose into anintermediate receptacle.
 4. The system of claim 1 wherein said unit doseis in the form of a discrete unit.
 5. The system of claim 1, whereinsaid device administers said unit dose onto the tongue of said patient.6. (canceled)
 7. The system of claim 1 wherein said multiparticulatesfurther comprise a pharmaceutically acceptable excipient.
 8. The systemof claim 7 wherein said excipient is coated with said drug.
 9. Thesystem of claim 7 wherein said drug is coated with said excipient. 10.The system of claim 7 wherein said excipient comprises a taste maskingagent.
 11. The system of claim 7 wherein said excipient comprises asweetening agent, flavoring agent or combination thereof.
 12. The systemof claim 7 wherein said excipient comprises a salivary stimulant, aneffervescent agent or a combination thereof.
 13. The system of claim 7wherein said excipient comprises a controlled release material.
 14. Thesystem of claim 13 wherein said excipient is less than about 20% byweight of said multiparticulates.
 15. The system of claim 1 wherein saidmultiple doses are contained in a reservoir.
 16. The system of claim 15further comprising a metering component to meter a unit dose of saiddrug from said reservoir upon actuation of said system. 17-23.(canceled)
 24. The system of claim 1 wherein said device comprises amouthpiece.
 25. The system of claim 24 wherein said mouthpiece is ofsufficient length to minimize moisture exposure of the multiparticulatesfrom outside the device.
 26. The system of claim 24 wherein said devicefurther comprises a mouthpiece cap to minimize moisture exposure of themultiparticulates from outside the device.
 27. The system of claim 1further comprising a desiccant to minimize moisture exposure of themultiparticulates from outside the device.
 28. The system of claim 1wherein said doses are individually metered prior to said actuation. 29.The system of claim 28 further comprising blisters on a substrate base,each blister containing said individually metered unit dose, saidblisters covered by a seal.
 30. The system of claim 29 wherein saidblisters are aligned linearly in the form of a strip.
 31. The system ofclaim 30 wherein said strip is in the form of a roll.
 32. A device fordelivery of a drug, for gastrointestinal deposition, comprising ahousing and an actuator, said device capable of containing multipledoses of multiparticulates comprising drug particles, said device uponactuation capable of delivering a unit dose of said multiparticulateswherein said drug particles have a mean diameter of greater than about50 μm to about 1 mm such that an effective dose of said drug cannot bedelivered into the lower lung of a human patient.
 33. The device ofclaim 32 wherein said delivery is by administering in vivo said unitdose into the oral cavity of said patient.
 34. The device of claim 32wherein said delivery is by dispensing ex vivo said unit dose into anintermediate receptacle.
 35. The device of claim 32 wherein said unitdose is in the form of a discrete unit.
 36. The device of claim 32wherein said device administers said unit dose onto the tongue of saidpatient. 37-48. (canceled)
 49. A method for delivery of a drug forgastrointestinal deposition, comprising delivering multiparticulatescomprising drug particles via the use of a multiple unit dosing devicecomprising a housing and an actuator, said device upon actuationdelivering a unit dose of said multiparticulates, and thereafterre-using said device to deliver additional unit doses of said drug atappropriate dosing intervals, said drug particles having a mean particlesize of greater than about 50 μm to about 1 mm such that an effectivedose of said drug cannot be delivered into the lower lung of a humanpatient.
 50. The method of claim 49 wherein said delivery is byadministering in vivo said unit dose into the oral cavity of a patient.51. (canceled)
 52. The method of claim 49 wherein said unit dose is inthe form of a discrete unit.
 53. The method of claim 49 wherein saiddevice administers said unit dose onto the tongue of said patient. 54.(canceled)
 55. A drug delivery device for administering a drug inmultiparticulate form into the oral cavity of a patient forgastrointestinal deposition, said device including a mouthpiece havingan outlet for delivering said multiparticulates and an inlet forreceiving said multiparticulates, wherein the mouthpiece protrudesdownward from the drug delivery device at an angle greater than about 15degrees measured from a horizontal baseline when the drug device is inan upright position, in order to direct the multiparticulates onto thetongue of said patient, said drug particles having a mean diameter ofgreater than 10 μm to about 1 mm.
 56. The mouthpiece of claim 55 whereinthe outlet of the mouthpiece faces downward to administer saidmultiparticulates onto the tongue of said patient.
 57. The mouthpiece ofclaim 55 wherein the mouthpiece is conical in shape and has an outlethaving a larger diameter than an inlet wherein the multiparticulatesenter said mouthpiece.
 58. The mouthpiece of claim 57 wherein thediameter of the outlet is 25% greater than the diameter of the inlet.59. The mouthpiece of claim 57 wherein the diameter of the outlet is 50%greater than the diameter of the inlet.
 60. The mouthpiece of claim 57wherein the diameter of the outlet is 100% greater than diameter of theinlet.
 61. The mouthpiece of claim 55 wherein the mouthpiece isrectangular in shape, having side walls which extend outward from aninlet at opposite angles, to provide an outlet having a larger area thanthe inlet area where the multiparticulates enter said mouthpiece. 62.The mouthpiece of claim 61 wherein the outlet area is 25% greater thanthe inlet area.
 63. The mouthpiece of claim 61 wherein the outlet areais 50% greater than the inlet area.
 64. The mouthpiece of claim 61wherein the outlet area is 100% greater than the inlet area.
 65. Themouthpiece of claim 61 having top and bottom walls which are convex ontheir outer edges. 66-68. (canceled)
 69. A device for deliveringmultiple unit doses of a drug in multiparticulate form, forgastrointestinal deposition, comprising a housing for containingmultiple unit doses of multiparticulates comprising drug particles, saidhousing having an opening for delivering a unit dose of saidmultiparticulates; said drug particles having a mean diameter of greaterthan 10 μm to about 1 mm; a metering component operable between a firstposition in which it receives a unit dose from said housing and a secondposition in which it delivers said unit dose to said opening in saidhousing; said unit dose being delivered from said metering component tothe exterior of the device through said opening of said housing with anair flow of less than about 20 litres/min.
 70. The device of claim 69wherein said device does not include a propellant to facilitate thedelivery of the unit dose.
 71. The device of claim 69 wherein said unitdose is delivered through said opening substantially by gravitationalforce. 72-84. (canceled)
 85. A device for delivering multiple unit dosesof a drug in multiparticulate form for gastrointestinal deposition,comprising a housing to contain multiple unit doses of a drug inmultiparticulate form comprising drug particles; said drug particleshaving a mean diameter of greater than about 50 μm to about 1 mm, saidhousing having a mouthpiece for delivering a unit dose of saidmultiparticulates into the oral cavity of a patient; means for removinga unit dose of said multiparticulates from said housing and transportingsaid unit dose to said mouthpiece, said mouthpiece having a drugreceiving end connected to said means and a drug delivery end throughwhich said unit dose is delivered outside the device, said mouthpiecebeing positioned on said device such that drug expelled through saidmouthpiece can be deposited in the oral cavity of a patientsubstantially without deposition of said particulates into the lungs ofsaid patient.
 86. A device for delivering multiple unit doses of a drugin multiparticulate form for gastrointestinal deposition, comprising ahousing to contain multiple unit doses of a drug in multiparticulateform comprising drug particles; said housing having a mouthpiece fordelivering a unit dose of said multiparticulates into the oral cavity ofa patient; a meterer for removing a unit dose of said multiparticulatesfrom said housing and transporting said unit dose to said mouthpiece,said mouthpiece having a drug receiving end connected to said meteringdevice and a drug delivery end through which said unit dose is deliveredoutside the device, said drug particles having a mean diameter ofgreater than about 50 μm to about 1 mm, said mouthpiece being positionedon said device such that drug expelled through said mouthpiece can bedeposited in the oral cavity of a patient substantially withoutdeposition of said particulates into the lungs of said patient. 87-91.(canceled)
 92. The system of claim 1, wherein said device comprises tworeservoirs, wherein one reservoir contains said medicament and the otherreservoir contains a liquid.
 93. The system of claim 92, wherein saiddevice comprises two reservoirs, wherein one reservoir contains saidmedicament and the other reservoir contains a liquid.
 94. The system ofclaim 92 wherein each reservoir has a dispensing hole and a retainingstrip, the retaining strip covering the dispensing hole and sealing saidthe reservoir when the retaining strip is in a first position, thedispensing hole being uncovered when the retaining strip is in a secondposition.
 95. The system of claim 92 wherein the reservoir isdisposable.
 96. The system of claim 92 wherein the reservoirs arepermanently affixed to one another.
 97. The system of claim 1, whereinsaid device comprises two reservoirs, each reservoir containing saidmedicament.
 98. The system of claim 1, wherein said device comprises tworeservoirs, wherein one reservoir contains said medicament and the otherreservoir contains a different medicament.
 99. The system of claim 97wherein each reservoir has a dispensing hole and a retaining strip, theretaining strip covering the dispensing hole and sealing said thereservoir when the retaining strip is in a first position, thedispensing hole being uncovered when the retaining strip is in a secondposition.
 100. The system of claim 97 wherein each reservoir isdisposable.
 101. The system of claim 97 wherein the reservoirs arepermanently affixed to one another.
 102. The system of claim 1, whereinsaid device further comprises: a disk, the disk having a plurality ofcavities arranged about on the periphery of the disk; the disk rotatingabout a central axis to position the cavities in alignment with apiercing member; and the piercing member for penetrating each of thecavities to expel a unit dose of said multiparticulates from the cavity.103. The system of claim 102 wherein the multiparticulates from thecavity are dispensed into a delivery conduit affixed to the piercingmember.
 104. The system of claim 102 wherein the delivery conduit iscoupled to a mouthpiece, the mouthpiece for dispensing the unit doseinto the oral cavity of the patient.
 105. The system of claim 103,wherein the delivery conduit comprises a hollow tube.
 106. The system ofclaim 104, wherein the delivery conduit comprises a hollow tube. 107.The system of claim 102 wherein the device is disposable.
 108. Thesystem of claim 102 wherein the disk is replaceable.
 109. The system ofclaim 1, wherein said device further comprises: a disk, the disk havinga plurality of blisters arranged about on the periphery of the disk,each blister comprising a premetered dose of the medicament; the diskrotating about a central axis to position each blister in alignment witha piercing member; and the piercing member for penetrating each alignedblister to expel the premetered dose from the aligned blister.
 110. Thesystem of claim 109 wherein the premetered dose from the blister isdispensed into a delivery conduit affixed to the piercing member. 111.The system of claim 110 wherein the delivery conduit is coupled to amouthpiece, the mouthpiece for dispensing the unit dose into the oralcavity of the patient.
 112. The system of claim 110, wherein thedelivery conduit comprises a hollow tube.
 113. The system of claim 111,wherein the delivery conduit comprises a hollow tube.
 114. The system ofclaim 1, wherein the medicament is stored in a plurality of containers,each container sealed via a removable seal.
 115. The system of claim 92wherein the medicament and the liquid are alternatively mixed within thedevice prior to administration.
 116. The system of claim 92 wherein saiddevice comprises two reservoirs, wherein one reservoir contains saidmedicament and the other reservoir contains a liquid, and wherein themedicament and the liquid are mixed in an intermediate receptacle. 117.The system of claim 97, wherein said device comprises two reservoirs,each of the reservoirs containing a different dose of said medicaments.